Nitrogen-containing heterocyclic compound

ABSTRACT

The present invention provides a compound having a cholinergic muscarinic M1 receptor positive allosteric modulator activity and useful as an agent for the prophylaxis or treatment of Alzheimer&#39;s disease, schizophrenia, pain, sleep disorder, Parkinson&#39;s disease dementia, dementia with Lewy bodies, and the like. 
     The present invention relates to a compound represented by the formula (I) or a salt thereof. 
                         
wherein each symbol is as described in the specification, or a salt thereof.

TECHNICAL FIELD

The present invention relates to a nitrogen-containing heterocycliccompound which has a cholinergic muscarinic M1 receptor positiveallosteric modulator activity and is useful as a medicament such as anagent for the prophylaxis or treatment of Alzheimer's disease,schizophrenia, pain, sleep disorder, Parkinson's disease dementia,dementia with Lewy bodies and the like. As used herein, the positiveallosteric modulator activity refers to an action to potentiate receptorfunction by binding at a different site from that of an endogenousactivator (acetylcholine for this receptor).

BACKGROUND OF THE INVENTION

Acetylcholine is a neurotransmitter that induces signal transduction inthe central nervous system and the neuromuscular connections (theparasympathetic nerve and motor nerve). In the central nervous system,nuclei of origin of the acetylcholine neuron are in the brain stem andforebrain, and those acetylcholine neurons project to cerebral cortex,hippocampus, and limbic area. In addition, some interneurons in somebrain areas such as striatum utilize acetylcholine as aneurotransmitter. Acetylcholine receptor is classified into a liganddependent-ion channel (cholinergic nicotinic receptor) and aG-protein-coupled receptor (cholinergic muscarinic receptor). Thecholinergic muscarinic receptor is one kind of receptor for excitatoryneurotransmitter, acetylcholine, and was named based on the selectiveactivation of the receptor by muscarine. The muscarinic receptor isfurther classified into subtypes of M1 to M5. The M1 receptor is knownto be mainly distributed in the brain, and deeply involved particularlyin learning, memory, sleep, neuropathic pain, and the like. Theimportance of cholinergic muscarinic M1 receptor in brain physiology iswell known, and a compound which enhances M1 receptor function isexpected to be useful as an agent for the prophylaxis or treatment ofmental diseases, neurodegenerative diseases, memory disorders, pain,sleep disorders, Parkinson's disease dementia, dementia with Lewy bodiesand the like (non-patent document 1).

WO 02/081447 A1 (Patent Document 1) discloses the following compound asa compound having a tumor necrosis factor-α (TNF-α) or a cAMPphosphodiesterase IV (PDE4) inhibitory activity and useful for theprophylaxis or treatment of inflammation and autoimmune disease.

wherein each symbol is as defined in the document.

WO 02/081446 A1 (Patent Document 2) discloses the following compound asa compound having a tumor necrosis factor-α (TNF-α) or a cAMPphosphodiesterase IV (PDE4) inhibitory activity and useful for theprophylaxis or treatment of inflammation and autoimmune disease.

wherein each symbol is as defined in the document.

WO 2006/020879 A1 (Patent Document 3) discloses the following compoundas a glutamic acid receptor potentiator useful for the prophylaxis ortreatment of psychoneurotic disorder associated with glutamatedysfunction.

wherein each symbol is as defined in the document.

WO 2013/063549 A1 (Patent Document 4) discloses the following compoundas a compound useful for the prophylaxis or treatment of psychoneuroticdisorder associated with muscarinic acetylcholine receptor dysfunction.

wherein each symbol is as defined in the document.

Bioorganic & Medicinal Chemistry Letters, 20 (2010) 1792-1975(Non-Patent Document 2) discloses the following compound as an M1receptor positive allosteric modulator.

Gordon, C. P., Byrne, N., McCluskey, A. Green Chem., 2010, 12,1000-1006. (Non-Patent Document 3) discloses the following compoundsimilar to the compound of the present invention.

WO 2010/096338 A1 (Patent Document 5) discloses the following compoundas an M1 receptor positive allosteric modulator useful for theprophylaxis or treatment of a Alzheimer's disease, schizophrenia, painor sleep disorder.

wherein each symbol is as defined in the document.

WO 95/030647 A1 (Patent Document 6) discloses the following compoundsimilar to the compound of the present invention.

wherein each symbol is as defined in the document.

WO 2007/139464 A1 (Patent Document 7) discloses the following compoundas a CB₁ receptor ligand useful for the prophylaxis or treatment ofpain, cancer, multiple sclerosis, Parkinson's disease, Huntington'sdisease, Alzheimer's disease, anxiety disorder, gastrointestinaldisorder and cardiovascular disorder.

wherein each symbol is as defined in the document.

US 2008/0108659 A1 (Patent Document 8) discloses the following compoundas a compound having poly(ADP ribose) polymerase (PARP) activity anduseful for the prophylaxis or treatment of cancer, central nervoussystem disease, inflammation disease and the like.

wherein each symbol is as defined in the document.

WO 2011/006794 A1 (Patent Document 9) discloses the following compoundas a compound selectively inhibiting an activity of poly (ADP-ribose)polymerase PARP-1 with respect to poly (ADP-ribose) polymerase PARP-2and useful for the prophylaxis or treatment of cancer, cardiovasculardisorder, central nervous system disorder and the like.

wherein each symbol is as defined in the document.

WO 2012/003147 A1 (Patent Document 10) discloses the following compoundas a compound having an M1PAM activity and useful for the prophylaxis ortreatment of Alzheimer's disease, schizophrenia, pain, sleep disorderand the like.

wherein each symbol is as defined in the document.

WO 2012/158475 A1 (Patent Document 11) discloses the following compoundas a compound having an M1PAM activity and useful for the prophylaxis ortreatment of Alzheimer's disease and other diseases.

wherein each symbol is as defined in the document.

JP-B-S44-16647 (Patent Document 12) discloses the following compoundsimilar to the compound of the present invention.

DOCUMENT LIST Patent Document

-   Patent Document 1: WO 02/081447 A1-   Patent Document 2: WO 02/081446 A1-   Patent Document 3: WO 2006/020879 A1-   Patent Document 4: WO 2013/063549 A1-   Patent Document 5: WO 2010/096338 A1-   Patent Document 6: WO 95/030647 A1-   Patent Document 7: WO 2007/139464 A1-   Patent Document 8: US 2008/0108659 A1-   Patent Document 9: WO 2011/006794 A1-   Patent Document 10: WO 2012/003147 A1-   Patent Document 11: WO 2012/158475 A1-   Patent Document 12: JP-B-S44-16647

Non-Patent Document

-   Non-Patent Document 1: Nature Reviews Drug Discovery, 2007, 6,    721-733.-   Non-Patent Document 2: Bioorganic & Medicinal Chemistry Letters,    20 (2010) 1792-1975.-   Non-Patent Document 3: Gordon, C. P., Byrne, N., McCluskey, A. Green    Chem., 2010, 12, 1000-1006.

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The development of a compound having a cholinergic muscarinic M1receptor (M1 receptor) positive allosteric modulator activity and usefulas an agent for the prophylaxis or treatment of for Alzheimer's disease,schizophrenia, pain, sleep disorder, Parkinson's disease dementia,dementia with Lewy bodies and the like is desired. As used herein, thepositive allosteric modulator activity refers to an action to potentiatereceptor function by binding at a different site from that of anendogenous activator (acetylcholine for this receptor).

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt tosolve the aforementioned problems and found that a compound representedby the following formula (I) has a cholinergic muscarinic M1 receptorpositive allosteric modulator activity, which resulted in the completionof the present invention.

Accordingly, the present invention relates to the following.

[1]A compound represented by the formula (I):

wherein

R¹ is an optionally substituted 5- or 6-membered cyclic group or anoptionally substituted C₁₋₆ alkyl group;

R² and R³ are the same or different and each is a hydrogen atom, ahalogen atom, a cyano group, an optionally substituted C₁₋₆ alkyl group,an optionally substituted C₁₋₆ alkoxy group or an optionally substitutedC₃₋₆ cycloalkyl group;

R⁴ is a halogen atom, a cyano group, an optionally substituted C₁₋₆alkyl group, an optionally substituted C₁₋₆ alkoxy group, an optionallysubstituted carbamoyl group or an optionally substituted 3- to8-membered cyclic group; and

Ring A is an optionally further substituted 6-membered aromatic ring,

or a salt thereof (in the present specification, to be referred ascompound (1)).

[2] The compound of the above-mentioned [1], wherein R¹ is

(1) an optionally substituted phenyl group,

(2) an optionally substituted C₅₋₆ cycloalkyl group,

(3) an optionally substituted 5- or 6-membered non-aromatic heterocyclicgroup,

(4) an optionally substituted 5- or 6-membered monocyclic aromaticheterocyclic group, or

(5) an optionally substituted C₁₋₆ alkyl group,

or a salt thereof.

[3] The compound of the above-mentioned [1] or [2], wherein R⁴ is

(1) a halogen atom,

(2) a cyano group,

(3) a C₁₋₆ alkyl group,

(4) an optionally substituted C₁₋₆ alkoxy group,

(5) an optionally substituted carbamoyl group, or

(6) an optionally substituted 5- or 6-membered monocyclic aromaticheterocyclic group, or a salt thereof.

[4] The compound of any of the above-mentioned [1] to [3], wherein RingA is a 6-membered aromatic ring optionally further substituted by 1 to 3substituents, in addition to R⁴, selected from

(a) a halogen atom,

(b) a C₁₋₆ alkyl group, and

(c) a C₁₋₆ alkoxy group,

or a salt thereof.

[5] The compound of any of the above-mentioned [1] to [4], wherein

R¹ is

(1) an optionally substituted phenyl group,

(2) an optionally substituted C₅₋₆ cycloalkyl group,

(3) an optionally substituted 5- or 6-membered non-aromatic heterocyclicgroup,

(4) an optionally substituted 5- or 6-membered monocyclic aromaticheterocyclic group, or

(5) an optionally substituted C₁₋₆ alkyl group;

R² is

(1) a hydrogen atom,

(2) a halogen atom, or

(3) an optionally substituted C₁₋₆ alkyl group;

R³ is

(1) a hydrogen atom,

(2) a halogen atom,

(3) a cyano group,

(4) an optionally substituted C₁₋₆ alkyl group,

(5) a C₁₋₆ alkoxy group, or

(6) a C₃₋₆ cycloalkyl group;

R⁴ is

(1) a halogen atom,

(2) a cyano group,

(3) a C₁₋₆ alkyl group,

(4) an optionally substituted C₁₋₆ alkoxy group,

(5) an optionally substituted carbamoyl group, or

(6) an optionally substituted 5- or 6-membered monocyclic aromaticheterocyclic group; and

Ring A is a 6-membered aromatic ring optionally further substituted by 1to 3 substituents, in addition to R⁴, selected from

(a) a halogen atom,

(b) a C₁₋₆ alkyl group, and

(c) a C₁₋₆ alkoxy group,

or a salt thereof.

[6] The compound of any of the above-mentioned [1] to [5], wherein

R¹ is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(i) a halogen atom, and

(ii) a cyano group,

(2) a C₅₋₆ cycloalkyl group optionally substituted by 1 to 3substituents selected from

-   -   (i) a hydroxy group,    -   (ii) a C₁₋₆ alkyl group optionally substituted by 1 to 3 hydroxy        groups, and    -   (iii) a C₁₋₆ alkoxy group,        (3) a 5- or 6-membered monocyclic non-aromatic heterocyclic        group optionally substituted by 1 to 3 hydroxy groups,        (4) a 5- or 6-membered monocyclic aromatic heterocyclic group        optionally substituted by 1 to 3 halogen atoms, or        (5) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from    -   (i) a hydroxy group, and    -   (ii) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group;

R² is

(1) a hydrogen atom,

(2) a halogen atom, or

(3) a C₁₋₆ alkyl group;

R³ is

(1) a hydrogen atom,

(2) a halogen atom,

(3) a cyano group,

(4) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen atoms,

(5) a C₁₋₆ alkoxy group, or

(6) a C₃₋₆ cycloalkyl group;

R⁴ is

(1) a halogen atom,

(2) a cyano group,

(3) a C₁₋₆ alkyl group,

(4) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen atoms,

(5) a carbamoyl group,

(6) a mono- or di-C₁₋₆ alkyl-carbamoyl group, or

(7) a 5- or 6-membered monocyclic aromatic heterocyclic group optionallysubstituted by 1 to 3 C₁₋₆ alkyl groups; and

Ring A is a 6-membered aromatic ring optionally further substituted by 1to 3 substituents, in addition to R⁴, selected from

(a) a halogen atom,

(b) a C₁₋₆ alkyl group, and

(c) a C₁₋₆ alkoxy group,

or a salt thereof.

[7] The compound of the above-mentioned [6], wherein the partialstructure represented by the following formula:

in the formula (I) is a partial structure represented by the followingformula:

or a salt thereof.[8] The compound of any of the above-mentioned [1] to [7], wherein

R¹ is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(i) a halogen atom, and

(ii) a cyano group,

(2) a C₅₋₆ cycloalkyl group optionally substituted by 1 to 3 hydroxygroups,

(3) a 5- or 6-membered monocyclic non-aromatic heterocyclic groupoptionally substituted by 1 to 3 hydroxy groups, or

(4) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (i) a hydroxy group, and    -   (ii) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group;

R² is

(1) a hydrogen atom,

(2) a halogen atom, or

(3) a C₁₋₆ alkyl group;

R³ is

(1) a hydrogen atom,

(2) a halogen atom,

(3) a cyano group,

(4) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen atoms,

(5) a C₁₋₆ alkoxy group, or

(6) a C₃₋₆ cycloalkyl group;

R⁹ is

(1) a halogen atom,

(2) a cyano group,

(3) a C₁₋₆ alkyl group,

(4) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen atoms,

(5) a mono- or di-C₁₋₆ alkyl-carbamoyl group, or

(6) a 5- or 6-membered monocyclic aromatic heterocyclic group optionallysubstituted by 1 to 3 C₁₋₆ alkyl groups; and

Ring A is a 6-membered aromatic ring optionally further substituted by 1to 3 substituents, in addition to R⁴, selected from

(a) a halogen atom, and

(b) a C₁₋₆ alkoxy group,

or a salt thereof.

[9] The compound of the above-mentioned [8], wherein the partialstructure represented by the following formula:

in the formula (I) is a partial structure represented by the followingformula:

or a salt thereof.[10] The compound of any of the above-mentioned [1] to [9], wherein

R¹ is

(1) a C₅₋₆ cycloalkyl group optionally substituted by 1 to 3 hydroxygroups, or

(2) a 5- or 6-membered monocyclic non-aromatic heterocyclic groupoptionally substituted by 1 to 3 hydroxy groups;

R² is

(1) a halogen atom, or

(2) a C₁₋₆ alkyl group;

R³ is a C₁₋₆ alkyl group;

R⁴ is

(1) a C₁₋₆ alkyl group,

(2) a C₁₋₆ alkoxy group, or

(3) a 5- or 6-membered monocyclic aromatic heterocyclic group; and

Ring A is a benzene ring or a pyridine ring, each of which isunsubstituted, in addition to R⁴,

or a salt thereof.

[11] The compound of the above-mentioned [10], wherein the partialstructure represented by the following formula:

in the formula (I) is a partial structure represented by the followingformula:

or a salt thereof.[12] The compound of any of the above-mentioned [1] to [11], wherein

R¹ is

(1) a cyclohexyl group substituted by one hydroxy group, or

(2) a tetrahydropyranyl group substituted by one hydroxy group;

R² is

(1) a halogen atom, or

(2) a C₁₋₆ alkyl group;

R³ is a C₁₋₆ alkyl group;

R⁴ is

(1) a C₁₋₆ alkyl group,

(2) a C₁₋₆ alkoxy group, or

(3) a pyrazolyl group; and

Ring A is a benzene ring or a pyridine ring, each of which isunsubstituted, in addition to R⁴,

or a salt thereof.

[13] The compound of the above-mentioned [12], wherein the partialstructure represented by the following formula:

in the formula (I) is a partial structure represented by the followingformula:

or a salt thereof.[14]2-[(3S,4S)-4-Hydroxytetrahydro-2H-pyran-3-yl]-6-(4-methoxybenzyl)-4,5-dimethyl-2,3-dihydro-1H-isoindol-1-one,or a salt thereof.[15]4-Fluoro-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindol-1-one,or a salt thereof.[16]2-((1S,2S)-2-Hydroxycyclohexyl)-4,5-dimethyl-6-(6-methylpyridin-3-yl)methyl)isoindolin-1-one,or a salt thereof.[17]A medicament comprising the compound of any of the above-mentioned[1] to [16] or a salt thereof.[18] The medicament of the above-mentioned [17], which is a cholinergicmuscarinic M1 receptor positive allosteric modulator.[19] The medicament of the above-mentioned [17], which is an agent forthe prophylaxis or treatment of Alzheimer's disease, schizophrenia,pain, sleep disorder, Parkinson's disease dementia or dementia with Lewybodies.[20] The compound of any of the above-mentioned [1] to [16] or a saltthereof for use in the prophylaxis or treatment of Alzheimer's disease,schizophrenia, pain, sleep disorder, Parkinson's disease dementia ordementia with Lewy bodies.[21]A method of cholinergic muscarinic M1 receptor positive allostericmodulation in a mammal, which comprises administering an effectiveamount of the compound of any of the above-mentioned [1] to [16] or asalt thereof to the mammal.[22]A method for the prophylaxis or treatment of Alzheimer's disease,schizophrenia, pain, sleep disorder, Parkinson's disease dementia ordementia with Lewy bodies in a mammal, which comprises administering aneffective amount of the compound of any of the above-mentioned [1] to[16] or a salt thereof to the mammal.[23] Use of the compound of any of the above-mentioned [1] to [16] or asalt thereof for the production of an agent for the prophylaxis ortreatment of Alzheimer's disease, schizophrenia, pain, sleep disorder,Parkinson's disease dementia or dementia with Lewy bodies.

Effect of the Invention

The compound of the present invention has a cholinergic muscarinic M1receptor positive allosteric modulator activity, and is useful as anagent for the prophylaxis or treatment of, for example, Alzheimer'sdisease, schizophrenia, pain, sleep disorder, Parkinson's diseasedementia, dementia with Lewy bodies and the like.

DETAILED DESCRIPTION OF THE INVENTION

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5 halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5 halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₆₋₁₄ aryl group” includephenyl, l-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5 halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5 halogen atoms. Specific examples thereof includemethylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5 halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, l-naphthoyl and 2-naphthoyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonylgroup” include phenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C₁₋₆alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₇₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5 halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, l-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following Substituent Group A.

[Substituent Group A]

(1) a halogen atom,

(2) a nitro group,

(3) a cyano group,

(4) an oxo group,

(5) a hydroxy group,

(6) an optionally halogenated C₁₋₆ alkoxy group,

(7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),

(8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),

(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,pyridyloxy),

(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,morpholinyloxy, piperidinyloxy),

(11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),

(12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,2-naphthoyloxy),

(13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),

(14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy),

(15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy),

(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g.,nicotinoyloxy),

(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group(e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),

(18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,methylsulfonyloxy, trifluoromethylsulfonyloxy),

(19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),

(20) an optionally halogenated C₁₋₆ alkylthio group,

(21) a 5- to 14-membered aromatic heterocyclic group,

(22) a 3- to 14-membered non-aromatic heterocyclic group,

(23) a formyl group,

(24) a carboxy group,

(25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,

(26) a C₆₋₁₄ aryl-carbonyl group,

(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,

(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,

(29) a C₁₋₆ alkoxy-carbonyl group,

(30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),

(31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl),

(32) a carbamoyl group,

(33) a thiocarbamoyl group,

(34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,

(35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),

(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl, thienylcarbamoyl),

(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g.,morpholinylcarbamoyl, piperidinylcarbamoyl),

(38) an optionally halogenated C₁₋₆ alkylsulfonyl group,

(39) a C₆₋₁₄ arylsulfonyl group,

(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,pyridylsulfonyl, thienylsulfonyl),

(41) an optionally halogenated C₁₋₆ alkylsulfinyl group,

(42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl),

(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl),

(44) an amino group,

(45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino, ethylamino,propylamino, isopropylamino, butylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, N-ethyl-N-methylamino),

(46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),

(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,pyridylamino),

(48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),

(49) a formylamino group,

(50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,propanoylamino, butanoylamino),

(51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,N-acetyl-N-methylamino),

(52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino),

(53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,tert-butoxycarbonylamino),

(54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,benzyloxycarbonylamino),

(55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino),

(56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),

(57) an optionally halogenated C₁₋₆ alkyl group,

(58) a C₂₋₆ alkenyl group,

(59) a C₂₋₆ alkynyl group,

(60) a C₃₋₁₀ cycloalkyl group,

(61) a C₃₋₁₀ cycloalkenyl group and

(62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” include 5- or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromaticheterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,1-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and 9- to 14-membered fused polycyclic (preferably bi ortricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include a “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the above-mentioned Substituent Group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g.,diallylcarbamoyl), a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆₋₁₄ arylsulfonyl group, a phosphono group and amono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from SubstituentGroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl)aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl)amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyl)aminogroup (e.g., benzylcarbamoyl)amino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonylamino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino) and a(C₁₋₆ alkyl) (C₆₋₁₄ aryl-carbonyl)amino group (e.g.,N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent Group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent Group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent Group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₋₆alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxyl group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from SubstituentGroup A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₄aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from Substituent Group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothic).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromSubstituent Group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl).

Each symbol in formula (I) is explained below.

R¹ is an optionally substituted 5- or 6-membered cyclic group or anoptionally substituted C₁₋₆ alkyl group.

Examples of the “5- or 6-membered cyclic group” of the “optionallysubstituted 5- or 6-membered cyclic group” for R¹ include a phenylgroup, a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl), a C₅₋₆cycloalkenyl group (cyclopentenyl, cyclohexenyl), a 5- or 6-memberedmonocyclic aromatic heterocyclic group, a 5- or 6-membered monocyclicnon-aromatic heterocyclic group and the like.

Examples of the “5- or 6-membered monocyclic aromatic heterocyclicgroup” exemplified as the “5- or 6-membered cyclic group” include a 5-or 6-membered monocyclic aromatic heterocyclic group containing, as aring-constituting atom so besides carbon atom, 1 to 4 heteroatomsselected from a nitrogen atom, a sulfur atom and an oxygen atom, andspecific examples thereof include those exemplified as the “5- to6-membered monocyclic aromatic heterocyclic group”, from among theabove-mentioned preferable examples of the “aromatic heterocyclicgroup”.

Examples of the “5- or 6-membered monocyclic non-aromatic heterocyclicgroup” exemplified as the “5- or 6-membered cyclic group” include a 5-or 6-membered monocyclic non-aromatic heterocyclic group containing, asa ring-constituting atom besides carbon atom, 1 to 4 heteroatomsselected from a nitrogen atom, a sulfur atom and an oxygen atom, andspecific examples thereof include 5- or 6-membered monocyclicnon-aromatic heterocyclic groups such as tetrahydrothienyl,tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl,imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl,thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl,tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl,dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl,tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl,tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl and the like.

The “C₁₋₆ alkyl group” of the “optionally substituted C₁₋₆ alkyl group”and the “5- or 6-membered cyclic group” of the “optionally substituted5- or 6-membered cyclic group” for R¹ each optionally has 1 to 5(preferably 1 to 3) substituents at substitutable position(s). Examplesof the substituent include the above-mentioned Substituent Group A. Whenthe number of the substituents is plural, the respective substituentsmay be the same or different.

R¹ is preferably

(1) an optionally substituted phenyl group,

(2) an optionally substituted C₅₋₆ cycloalkyl group,

(3) an optionally substituted 5- or 6-membered non-aromatic heterocyclicgroup,

(4) an optionally substituted 5- or 6-membered monocyclic aromaticheterocyclic group, or

(5) an optionally substituted C₁₋₆ alkyl group.

R¹ is more preferably

(1) a phenyl group, a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl), a5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) or a 5- or 6-membered monocyclic aromaticheterocyclic group (e.g., pyridyl), each of which is optionallysubstituted by 1 to 3 substituents selected from

-   -   (i) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (ii) a cyano group,    -   (iii) a hydroxy group,    -   (iv) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups, and    -   (v) a C₁₋₆ alkoxy group (e.g., methoxy), or        (2) a C₁₋₆ alkyl group (e.g., methyl, isobutyl,        1,2-dimethylpropyl) optionally substituted by 1 to 3        substituents selected from    -   (i) a hydroxy group, and    -   (ii) a 3- to 14-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group) (e.g., tetrahydrofuryl).

R¹ is further more preferably

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(i) a halogen atom (e.g., a fluorine atom), and

(ii) a cyano group,

(2) a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) optionallysubstituted by 1 to 3 substituents selected from

-   -   (i) a hydroxy group,    -   (ii) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups, and    -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),        (3) a 5- or 6-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl) optionally substituted by 1 to 3        hydroxy groups,        (4) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl) optionally substituted by 1 to 3 halogen atoms        (e.g., a fluorine atom, a chlorine atom), or        (5) a C₁₋₆ alkyl group (e.g., methyl, isobutyl,        1,2-dimethylpropyl) optionally substituted by 1 to 3        substituents selected from    -   (i) a hydroxy group, and    -   (ii) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydrofuryl).

R¹ is still more preferably

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(i) a halogen atom (e.g., a fluorine atom), and

(ii) a cyano group,

(2) a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) optionallysubstituted by 1 to 3 substituents selected from

-   -   (i) a hydroxy group,    -   (ii) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups, and    -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),        (3) a tetrahydropyranyl group optionally substituted by 1 to 3        hydroxy groups,        (4) a pyridyl group optionally substituted by 1 to 3 halogen        atoms (e.g., a fluorine atom, a chlorine atom), or        (5) a C₁₋₆ alkyl group (e.g., methyl, isobutyl,        1,2-dimethylpropyl) optionally substituted by 1 to 3        substituents selected from

(i) a hydroxy group, and

(ii) a tetrahydrofuryl group.

In another embodiment, R¹ is more preferably

(1) a phenyl group, a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl), a5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) or a 5- or 6-membered monocyclic aromaticheterocyclic group (e.g., pyridyl), each of which is optionallysubstituted by 1 to 3 substituents selected from

(i) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(ii) a cyano group, and

(iii) a hydroxy group, or

(2) a C₁₋₆ alkyl group (e.g., methyl, isobutyl, 1,2-dimethylpropyl)optionally substituted by 1 to 3 substituents selected from

-   -   (i) a hydroxy group, and    -   (ii) a 3- to 14-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group) (e.g., tetrahydrofuryl).

In this embodiment, R¹ is further more preferably

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(i) a halogen atom (e.g., a fluorine atom), and

(ii) a cyano group,

(2) a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) optionallysubstituted by 1 to 3 hydroxy groups,

(3) a 5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) optionally substituted by 1 to 3 hydroxy groups,

(4) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyridyl) optionally substituted by 1 to 3 halogen atoms (e.g., afluorine atom, a chlorine atom), or

(5) a C₁₋₆ alkyl group (e.g., methyl, isobutyl, 1,2-dimethylpropyl)optionally substituted by 1 to 3 substituents selected from

-   -   (i) a hydroxy group, and    -   (ii) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydrofuryl).

In this embodiment, R¹ is still more preferably

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(i) a halogen atom (e.g., a fluorine atom), and

(ii) a cyano group,

(2) a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) optionallysubstituted by 1 to 3 hydroxy groups,

(3) a tetrahydropyranyl group optionally substituted by 1 to 3 hydroxygroups,

(4) a pyridyl group optionally substituted by 1 to 3 halogen atoms(e.g., a fluorine atom, a chlorine atom), or

(5) a C₁₋₆ alkyl group (e.g., methyl, isobutyl, 1,2-dimethylpropyl)optionally substituted by 1 to 3 substituents selected from

(i) a hydroxy group, and

(ii) a tetrahydrofuryl group.

In another embodiment, R¹ is preferably

(1) an optionally substituted phenyl group,

(2) an optionally substituted C₅₋₆ cycloalkyl group,

(3) an optionally substituted 5- or 6-membered non-aromatic heterocyclicgroup, or

(4) an optionally substituted C₁₋₆ alkyl group.

In this embodiment, R¹ is more preferably

(1) a phenyl group, a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) ora 5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g.,tetrahydropyranyl), each of which is optionally substituted by 1 to 3substituents selected from

(i) a halogen atom (e.g., a fluorine atom),

(ii) a cyano group, and

(iii) a hydroxy group, or

(2) a C₁₋₆ alkyl group (e.g., methyl, isobutyl) optionally substitutedby 1 to 3 substituents selected from

-   -   (i) a hydroxy group, and    -   (ii) a 3- to 14-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group) (e.g., tetrahydrofuryl).

In this embodiment, R¹ is further more preferably

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(i) a halogen atom (e.g., a fluorine atom), and

(ii) a cyano group,

(2) a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) optionallysubstituted by 1 to 3 hydroxy groups,

(3) a 5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) optionally substituted by 1 to 3 hydroxy groups, or

(4) a C₁₋₆ alkyl group (e.g., methyl, isobutyl) optionally substitutedby 1 to 3 substituents selected from

-   -   (i) a hydroxy group, and    -   (ii) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydrofuryl).

In this embodiment, R¹ is still more preferably

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(i) a halogen atom (e.g., a fluorine atom), and

(ii) a cyano group,

(2) a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) optionallysubstituted by 1 to 3 hydroxy groups,

(3) a tetrahydropyranyl group optionally substituted by 1 to 3 hydroxygroups, or

(4) a C₁₋₆ alkyl group (e.g., methyl, isobutyl) optionally substitutedby 1 to 3 substituents selected from

(i) a hydroxy group, and

(ii) a tetrahydrofuryl group.

In another embodiment, R¹ is still more preferably

(1) a C₅₋₆ cycloalkyl group (e.g., cyclohexyl) optionally substituted by1 to 3 hydroxy groups, or

(2) a 5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) optionally substituted by 1 to 3 hydroxy groups.

In this embodiment, R¹ is even more preferably

(1) a C₅₋₆ cycloalkyl group (e.g., cyclohexyl) substituted by 1 to 3hydroxy groups, or

(2) a 5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) substituted by 1 to 3 hydroxy groups.

In this embodiment, R¹ is particularly preferably

(1) a cyclohexyl group substituted by one hydroxy group, or

(2) a tetrahydropyranyl group substituted by one hydroxy group.

R² and R³ are the same or different and each is a hydrogen atom, ahalogen atom, a cyano group, an optionally substituted C₁₋₆ alkyl group,an optionally substituted C₁₋₆ alkoxy group or an optionally substitutedC₃₋₆ cycloalkyl group.

Examples of the “C₃₋₆ cycloalkyl group” of the “optionally substitutedC₃₋₆ cycloalkyl group” for R² or R³ include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The “C₁₋₆ alkyl group” of the “optionally substituted C₁₋₆ alkyl group”,the “C₁₋₆ alkoxy group” of the “optionally substituted C₁₋₆ alkoxygroup” and the “C₃₋₆ cycloalkyl group” of the “optionally substitutedC₃₋₆ cycloalkyl group” for R² or R³ each optionally has 1 to 5(preferably 1 to 3) substituents at substitutable position(s). Examplesof the substituent include the above-mentioned Substituent Group A. Whenthe number of the substituents is plural, the respective substituentsmay be the same or different.

R² is preferably

(1) a hydrogen atom,

(2) a halogen atom (e.g., a fluorine atom, a chlorine atom), or

(3) an optionally substituted C₁₋₆ alkyl group (e.g., methyl).

R² is more preferably

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom, a fluorine atom), or

(3) a C₁₋₆ alkyl group (e.g., methyl).

R² is further more preferably

(1) a halogen atom (e.g., a fluorine atom), or

(2) a C₁₋₆ alkyl group (e.g., methyl).

R³ is preferably

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) an optionally substituted C₁₋₆ alkyl group (e.g., methyl, ethyl),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl).

R³ is more preferably

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 halogen atoms (e.g., a fluorine atom),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl).

R³ is further more preferably

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl).

R³ is particularly preferably a C₁₋₆ alkyl group (e.g., methyl).

R⁴ is a halogen atom, a cyano group, an optionally substituted C₁₋₆alkyl group, an optionally substituted C₁₋₆ alkoxy group, an optionallysubstituted carbamoyl group or an optionally substituted 3- to8-membered cyclic group.

Examples of the “3- to 8-membered cyclic group” of the “optionallysubstituted 3- to 8-membered cyclic group” for R⁴ include a phenylgroup, a C₃₋₈ cycloalkyl group, a C₃₋₈ cycloalkenyl group, a 5- or6-membered monocyclic aromatic heterocyclic group, a 3- to 8-memberedmonocyclic non-aromatic heterocyclic group and the like, and a 5- or6-membered monocyclic aromatic heterocyclic group is preferable.

Examples of the “C₃₋₈ cycloalkyl group” exemplified as theabove-mentioned “3- to 8-membered cyclic group” include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and thelike.

Examples of the “C₃₋₈ cycloalkenyl group” exemplified as theabove-mentioned “3- to 8-membered cyclic group” include cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl andcyclooctenyl.

Examples of the “5- or 6-membered monocyclic aromatic heterocyclicgroup” exemplified as the above-mentioned “3- to 8-membered cyclicgroup” include a 5- or 6-membered monocyclic aromatic heterocyclic groupcontaining, as a ring-constituting atom besides carbon atom, 1 to 4heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygenatom, and specific examples thereof include those exemplified as the “5-to 6-membered monocyclic aromatic heterocyclic group”, from among theabove-mentioned preferable examples of the “aromatic heterocyclicgroup”.

Examples of the “3- to 8-membered monocyclic non-aromatic heterocyclicgroup” exemplified as the above-mentioned “3- to 8-membered cyclicgroup” include a 3- to 8-membered monocyclic non-aromatic heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygenatom, and specific examples thereof include those exemplified as the “3-to 8-membered monocyclic non-aromatic heterocyclic group”, from amongthe above-mentioned preferable examples of the “non-aromaticheterocyclic group”.

The “C₁₋₆ alkyl group” of the “optionally substituted C₁₋₆ alkyl group”,the “C₁₋₆ alkoxy group” of the “optionally substituted C₁₋₆ alkoxygroup” and the “3- to 8-membered cyclic group” of the “optionallysubstituted 3- to 8-membered cyclic group” for R⁴ each optionally has 1to 5 (preferably 1 to 3) substituents at substitutable position(s).Examples of the substituent include the above-mentioned SubstituentGroup A. When the number of the substituents is plural, the respectivesubstituents may be the same or different.

R⁴ is preferably bonded to the carbon atom at the p-position(4-position) in the “6-membered aromatic ring” of the “optionallyfurther substituted 6-membered aromatic ring” for Ring A (i.e., at thep-position (4-position) relative to the binding site of theoxoisoindolinylmethyl in the formula (I)).

That is, the partial structure represented by the following formula:

in the formula (I) is preferably a partial structure represented by thefollowing formula:

R⁴ is preferably

(1) a halogen atom,

(2) a cyano group,

(3) a C₁₋₆ alkyl group,

(4) an optionally substituted C₁₋₆ alkoxy group,

(5) an optionally substituted carbamoyl group, or

(6) an optionally substituted 5- or 6-membered monocyclic aromaticheterocyclic group.

R⁴ is more preferably

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, isopropoxy) optionallysubstituted by 1 to 3 halogen atoms (e.g., a fluorine atom),

(5) a carbamoyl group,

(6) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl), or

(7) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, pyridyl, triazolyl, pyridazinyl) optionally substituted by 1to 3 C₁₋₆ alkyl groups (e.g., methyl).

R⁴ is further more preferably

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, isopropoxy) optionallysubstituted by 1 to 3 halogen atoms (e.g., a fluorine atom),

(5) a carbamoyl group,

(6) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl),

(7) a pyrazolyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl),

(8) a pyridyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl),

(9) a triazolyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl), or

(10) a pyridazinyl group optionally substituted by 1 to 3 C₁₋₆ alkylgroups (e.g., methyl).

In another embodiment, R⁴ is more preferably

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally substitutedby 1 to 3 halogen atoms (e.g., a fluorine atom),

(5) a carbamoyl group,

(6) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl), or

(7) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, pyridyl, triazolyl, pyridazinyl) optionally substituted by 1to 3 C₁₋₆ alkyl groups (e.g., methyl).

In this embodiment, R⁴ is further more preferably

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally substitutedby 1 to 3 halogen atoms (e.g., a fluorine atom),

(5) a carbamoyl group,

(6) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl),

(7) a pyrazolyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl),

(8) a pyridyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl),

(9) a triazolyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl), or

(10) a pyridazinyl group optionally substituted by 1 to 3 C₁₋₆ alkylgroups (e.g., methyl).

In another embodiment, R⁴ is more preferably

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom),

(5) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl), or

(6) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, pyridyl, triazolyl) optionally substituted by 1 to 3 C₁₋₆alkyl groups (e.g., methyl).

In this embodiment, R⁴ is further more preferably

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom),

(5) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl),

(6) a pyrazolyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl),

(7) a pyridyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl), or

(8) a triazolyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl).

In another embodiment, R⁴ is further more preferably

(1) a C₁₋₆ alkyl group (e.g., methyl),

(2) a C₁₋₆ alkoxy group (e.g., methoxy), or

(3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl).

R⁴ is particularly preferably

(1) a C₁₋₆ alkyl group (e.g., methyl),

(2) a C₁₋₆ alkoxy group (e.g., methoxy), or

(3) a pyrazolyl group.

Ring A is an optionally further substituted 6-membered aromatic ring.

Examples of the “6-membered aromatic ring” of the “optionally furthersubstituted 6-membered aromatic ring” for Ring A include a benzene ring,a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring,a triazine ring and the like, a benzene ring and a pyridine ring arepreferable.

The “6-membered aromatic ring” of the “optionally further substituted6-membered aromatic ring” for Ring A optionally has 1 to 4 (preferably 1to 3) substituents, in addition to R⁴, at substitutable position(s).Examples of the substituent include the above-mentioned SubstituentGroup A. When the number of the substituents is plural, the respectivesubstituents may be the same or different.

Ring A is preferably a 6-membered aromatic ring (e.g., a benzene ring, apyridine ring) optionally further substituted by 1 to 3 substituents, inaddition to R⁴, selected from

-   -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a C₁₋₆ alkyl group (e.g., methyl),    -   (c) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (d) a cyano group,    -   (e) a carbamoyl group,    -   (f) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,        methylcarbamoyl), and    -   (g) a 5- to 14-membered aromatic heterocyclic group (preferably        a 5- or 6-membered monocyclic aromatic heterocyclic group)        (e.g., pyrazolyl, triazolyl) optionally substituted by 1 to 3        C₁₋₆ alkyl groups (e.g., methyl).

Ring A is more preferably a 6-membered aromatic ring (e.g., a benzenering, a pyridine ring) optionally further substituted by 1 to 3substituents, in addition to R⁴, selected from

-   -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a C₁₋₆ alkyl group (e.g., methyl),    -   (c) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (d) a cyano group,    -   (e) a carbamoyl group,    -   (f) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,        methylcarbamoyl),    -   (g) a pyrazolyl group optionally substituted by 1 to 3 C₁₋₆        alkyl groups (e.g., methyl), and    -   (h) a triazolyl group optionally substituted by 1 to 3 C₁₋₆        alkyl groups (e.g., methyl).

Ring A is further more preferably

(1) a benzene ring optionally further substituted by 1 to 3substituents, in addition to R⁴, selected from

-   -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a C₁₋₆ alkyl group (e.g., methyl),    -   (c) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (d) a cyano group,    -   (e) a carbamoyl group,    -   (f) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,        methylcarbamoyl),    -   (g) a pyrazolyl group optionally substituted by 1 to 3 C₁₋₆        alkyl groups (e.g., methyl), and    -   (h) a triazolyl group optionally substituted by 1 to 3 C₁₋₆        alkyl groups (e.g., methyl), or        (2) a pyridine ring.

In another embodiment, Ring A is preferably a 6-membered aromatic ring(e.g., a benzene ring, a pyridine ring) optionally further substitutedby 1 to 3 substituents, in addition to R⁴, selected from

-   -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a C₁₋₆ alkyl group (e.g., methyl),    -   (c) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (d) a cyano group,    -   (e) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,        methylcarbamoyl), and    -   (f) a 5- to 14-membered aromatic heterocyclic group (preferably        a 5- or 6-membered monocyclic aromatic heterocyclic group)        (e.g., pyrazolyl).

In this embodiment, Ring A is more preferably a 6-membered aromatic ring(e.g., a benzene ring, a pyridine ring) optionally further substitutedby 1 to 3 substituents, in addition to R⁴, selected from

-   -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (c) a cyano group,    -   (d) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,        methylcarbamoyl), and    -   (e) a 5- to 14-membered aromatic heterocyclic group (preferably        a 5- or 6-membered monocyclic aromatic heterocyclic group)        (e.g., pyrazolyl).

In this embodiment, Ring A is further more preferably a 6-memberedaromatic ring (e.g., a benzene ring, a pyridine ring) optionally furthersubstituted by 1 to 3 substituents, in addition to R⁴, selected from

-   -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (c) a cyano group,    -   (d) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,        methylcarbamoyl), and    -   (e) a pyrazolyl group.

In this embodiment, Ring A is still more preferably

(1) a benzene ring optionally further substituted by 1 to 3substituents, in addition to R⁴, selected from

-   -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (c) a cyano group,    -   (d) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,        methylcarbamoyl), and    -   (e) a pyrazolyl group, or        (2) a pyridine ring.

In another embodiment, Ring A is preferably a 6-membered aromatic ring(e.g., a benzene ring, a pyridine ring) optionally further substitutedby 1 to 3 substituents, in addition to R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) a C₁₋₆ alkoxy group (e.g., methoxy).

In this embodiment, Ring A is more preferably

(1) a benzene ring optionally further substituted by 1 to 3substituents, in addition to R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) a C₁₋₆ alkoxy group (e.g., methoxy), or

(2) a pyridine ring.

In another embodiment, Ring A is preferably a 6-membered aromatic ring(e.g., a benzene ring, a pyridine ring) optionally further substitutedby 1 to 3 substituents, in addition to R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a C₁₋₆ alkoxy group (e.g., methoxy).

In this embodiment, Ring A is more preferably

(1) a benzene ring optionally further substituted by 1 to 3substituents, in addition to R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a C₁₋₆ alkoxy group (e.g., methoxy), or

(2) a pyridine ring.

Ring A is particularly preferably a benzene ring or a pyridine ring,each of which is unsubstituted, in addition to R⁴.

Preferable examples of compound (I) include the following compounds.

[Compound A-1]

Compound (I) wherein

R¹ is

(1) an optionally substituted phenyl group,

(2) an optionally substituted C₅₋₆ cycloalkyl group,

(3) an optionally substituted 5- or 6-membered non-aromatic heterocyclicgroup,

(4) an optionally substituted 5- or 6-membered monocyclic aromaticheterocyclic group, or

(5) an optionally substituted C₁₋₆ alkyl group;

R² is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a fluorine atom, a chlorine atom), or

(3) an optionally substituted C₁₋₆ alkyl group (e.g., methyl);

R³ is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) an optionally substituted C₁₋₆ alkyl group (e.g., methyl, ethyl),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl);

R⁴ is

(1) a halogen atom,

(2) a cyano group,

(3) a C₁₋₆ alkyl group,

(4) an optionally substituted C₁₋₆ alkoxy group,

(5) an optionally substituted carbamoyl group, or

(6) an optionally substituted 5- or 6-membered monocyclic aromaticheterocyclic group; and

Ring A is a 6-membered aromatic ring (e.g., a benzene ring, a pyridinering) optionally further substituted by 1 to 3 substituents, in additionto R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) a C₁₋₆ alkoxy group (e.g., methoxy).

In [Compound A-1], the partial structure represented by the followingformula:

in the formula (I) is preferably a partial structure represented by thefollowing formula:

[Compound A-2]

Compound (I) wherein

R¹ is

(1) a phenyl group, a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl), a5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) or a 5- or 6-membered monocyclic aromaticheterocyclic group (e.g., pyridyl), each of which is optionallysubstituted by 1 to 3 substituents selected from

-   -   (i) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (ii) a cyano group,    -   (iii) a hydroxy group,    -   (iv) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups, and    -   (v) a C₁₋₆ alkoxy group (e.g., methoxy), or        (2) a C₁₋₆ alkyl group (e.g., methyl, isobutyl,        1,2-dimethylpropyl) optionally substituted by 1 to 3        substituents selected from    -   (i) a hydroxy group, and    -   (ii) a 3- to 14-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group) (e.g., tetrahydrofuryl);

R² is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom, a fluorine atom), or

(3) a C₁₋₆ alkyl group (e.g., methyl);

R³ is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 halogen atoms (e.g., a fluorine atom),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl);

R⁴ is

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, isopropoxy) optionallysubstituted by 1 to 3 halogen atoms (e.g., a fluorine atom),

(5) a carbamoyl group,

(6) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl), or

(7) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, pyridyl, triazolyl, pyridazinyl) optionally substituted by 1to 3 C₁₋₆ alkyl groups (e.g., methyl); and

Ring A is a 6-membered aromatic ring (e.g., a benzene ring, a pyridinering) optionally further substituted by 1 to 3 substituents, in additionto R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) a C₁₋₆ alkoxy group (e.g., methoxy).

In [Compound A-2], the partial structure represented by the followingformula:

in the formula (I) is preferably a partial structure represented by thefollowing formula:

[Compound A-3]

Compound (I) wherein

R¹ is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(i) a halogen atom (e.g., a fluorine atom), and

(ii) a cyano group,

(2) a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) optionallysubstituted by 1 to 3 substituents selected from

-   -   (i) a hydroxy group,    -   (ii) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups, and    -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),        (3) a 5- or 6-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl) optionally substituted by 1 to 3        hydroxy groups,        (4) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl) optionally substituted by 1 to 3 halogen atoms        (e.g., a fluorine atom, a chlorine atom), or        (5) a C₁₋₆ alkyl group (e.g., methyl, isobutyl,        1,2-dimethylpropyl) optionally substituted by 1 to 3        substituents selected from    -   (i) a hydroxy group, and    -   (ii) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydrofuryl);

R² is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom, a fluorine atom), or

(3) a C₁₋₆ alkyl group (e.g., methyl);

R³ is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 halogen atoms (e.g., a fluorine atom),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl);

R⁴ is

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, isopropoxy) optionallysubstituted by 1 to 3 halogen atoms (e.g., a fluorine atom),

(5) a carbamoyl group,

(6) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl), or

(7) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, pyridyl, triazolyl, pyridazinyl) optionally substituted by 1to 3 C₁₋₆ alkyl groups (e.g., methyl); and

Ring A is a 6-membered aromatic ring (e.g., a benzene ring, a pyridinering) optionally further substituted by 1 to 3 substituents, in additionto R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) a C₁₋₆ alkoxy group (e.g., methoxy).

In [Compound A-3], the partial structure represented by the followingformula:

in the formula (I) is preferably a partial structure represented by thefollowing formula:

[Compound A-4]

Compound (I) wherein

R¹ is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(i) a halogen atom (e.g., a fluorine atom), and

(ii) a cyano group,

(2) a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) optionallysubstituted by 1 to 3 substituents selected from

-   -   (i) a hydroxy group,    -   (ii) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups, and    -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy),        (3) a tetrahydropyranyl group optionally substituted by 1 to 3        hydroxy groups,        (4) a pyridyl group optionally substituted by 1 to 3 halogen        atoms (e.g., a fluorine atom, a chlorine atom), or        (5) a C₁₋₆ alkyl group (e.g., methyl, isobutyl,        1,2-dimethylpropyl) optionally substituted by 1 to 3        substituents selected from

(i) a hydroxy group, and

(ii) a tetrahydrofuryl group;

R² is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom, a fluorine atom), or

(3) a C₁₋₆ alkyl group (e.g., methyl);

R³ is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 halogen atoms (e.g., a fluorine atom),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl);

R⁴ is

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, isopropoxy) optionallysubstituted by 1 to 3 halogen atoms (e.g., a fluorine atom),

(5) a carbamoyl group,

(6) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl),

(7) a pyrazolyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl),

(8) a pyridyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl),

(9) a triazolyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl), or

(10) a pyridazinyl group optionally substituted by 1 to 3 C₁₋₆ alkylgroups (e.g., methyl); and

Ring A is

(1) a benzene ring optionally further substituted by 1 to 3substituents, in addition to R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) a C₁₋₆ alkoxy group (e.g., methoxy), or

(2) a pyridine ring.

In [Compound A-4], the partial structure represented by the followingformula:

in the formula (I) is preferably a partial structure represented by thefollowing formula:

[Compound B-1]

Compound (I) wherein

R¹ is

(1) a phenyl group, a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl), a5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) or a 5- or 6-membered monocyclic aromaticheterocyclic group (e.g., pyridyl), each of which is optionallysubstituted by 1 to 3 substituents selected from

(i) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(ii) a cyano group, and

(iii) a hydroxy group, or

(2) a C₁₋₆ alkyl group (e.g., methyl, isobutyl, 1,2-dimethylpropyl)optionally substituted by 1 to 3 substituents selected from

-   -   (i) a hydroxy group, and    -   (ii) a 3- to 14-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group) (e.g., tetrahydrofuryl);

R² is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom, a fluorine atom), or

(3) a C₁₋₆ group (e.g., methyl);

R³ is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 halogen atoms (e.g., a fluorine atom),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl);

R⁴ is

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally substitutedby 1 to 3 halogen atoms (e.g., a fluorine atom),

(5) a carbamoyl group,

(6) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl), or

(7) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, pyridyl, triazolyl, pyridazinyl) optionally substituted by 1to 3 C₁₋₆ alkyl groups (e.g., methyl); and

Ring A is a 6-membered aromatic ring (e.g., a benzene ring, a pyridinering) optionally further substituted by 1 to 3 substituents, in additionto R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) a C₁₋₆ alkoxy group (e.g., methoxy).

In [Compound B-1], the partial structure represented by the followingformula:

in the formula (I) is preferably a partial structure represented by thefollowing formula:

[Compound B-2]

Compound (I) wherein

R¹ is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(i) a halogen atom (e.g., a fluorine atom), and

(ii) a cyano group,

(2) a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) optionallysubstituted by 1 to 3 hydroxy groups,

(3) a 5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) optionally substituted by 1 to 3 hydroxy groups,

(4) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyridyl) optionally substituted by 1 to 3 halogen atoms (e.g., afluorine atom, a chlorine atom), or

(5) a C₁₋₆ alkyl group (e.g., methyl, isobutyl, 1,2-dimethylpropyl)optionally substituted by 1 to 3 substituents selected from

-   -   (i) a hydroxy group, and    -   (ii) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydrofuryl);

R² is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom, a fluorine atom), or

(3) a C₁₋₆ alkyl group (e.g., methyl);

R³ is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 halogen atoms (e.g., a fluorine atom),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl);

R⁴ is

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally substitutedby 1 to 3 halogen atoms (e.g., a fluorine atom),

(5) a carbamoyl group,

(6) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl), or

(7) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, pyridyl, triazolyl, pyridazinyl) optionally substituted by 1to 3 C₁₋₆ alkyl groups (e.g., methyl); and

Ring A is a 6-membered aromatic ring (e.g., a benzene ring, a pyridinering) optionally further substituted by 1 to 3 substituents, in additionto R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) a C₁₋₆ alkoxy group (e.g., methoxy).

In [Compound B-2], the partial structure represented by the followingformula:

in the formula (I) is preferably a partial structure represented by thefollowing formula:

[Compound B-3]

Compound (I) wherein

R¹ is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(i) a halogen atom (e.g., a fluorine atom), and

(ii) a cyano group,

(2) a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) optionallysubstituted by 1 to 3 hydroxy groups,

(3) a tetrahydropyranyl group optionally substituted by 1 to 3 hydroxygroups,

(4) a pyridyl group optionally substituted by 1 to 3 halogen atoms(e.g., a fluorine atom, a chlorine atom), or

(5) a C₁₋₆ alkyl group (e.g., methyl, isobutyl, 1,2-dimethylpropyl)optionally substituted by 1 to 3 substituents selected from

(i) a hydroxy group, and

(ii) a tetrahydrofuryl group;

R² is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom, a fluorine atom), or

(3) a C₁₋₆ alkyl group (e.g., methyl);

R³ is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1to 3 halogen atoms (e.g., a fluorine atom),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl);

R⁴ is

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl, ethyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally substitutedby 1 to 3 halogen atoms (e.g., a fluorine atom),

(5) a carbamoyl group,

(6) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl),

(7) a pyrazolyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl),

(8) a pyridyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl),

(9) a triazolyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl), or

(10) a pyridazinyl group optionally substituted by 1 to 3 C₁₋₆ alkylgroups (e.g., methyl); and

Ring A is

(1) a benzene ring optionally further substituted by 1 to 3substituents, in addition to R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom),

(b) a C₁₋₆ alkyl group (e.g., methyl), and

(c) a C₁₋₆ alkoxy group (e.g., methoxy), or

(2) a pyridine ring.

In [Compound B-3], the partial structure represented by the followingformula:

in the formula (I) is preferably a partial structure represented by thefollowing formula:

[Compound C-1]

Compound (I) wherein

R¹ is

(1) an optionally substituted phenyl group,

(2) an optionally substituted C₅₋₆ cycloalkyl group,

(3) an optionally substituted 5- or 6-membered non-aromatic heterocyclicgroup, or

(4) an optionally substituted C₁₋₆ alkyl group;

R² is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a fluorine atom, a chlorine atom), or

(3) an optionally substituted C₁₋₆ alkyl group (e.g., methyl);

R³ is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) an optionally substituted C₁₋₆ alkyl group (e.g., methyl),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl);

R⁴ is

(1) a halogen atom,

(2) a cyano group,

(3) a C₁₋₆ alkyl group,

(4) an optionally substituted C₁₋₆ alkoxy group,

(5) an optionally substituted carbamoyl group, or

(6) an optionally substituted 5- or 6-membered monocyclic aromaticheterocyclic group; and

Ring A is a 6-membered aromatic ring (e.g., a benzene ring, a pyridinering) optionally further substituted by 1 to 3 substituents, in additionto R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a C₁₋₆ alkoxy group (e.g., methoxy).

[Compound Ca-1]

Compound (I) wherein

R¹ is

(1) an optionally substituted phenyl group,

(2) an optionally substituted C₅₋₆ cycloalkyl group,

(3) an optionally substituted 5- or 6-membered non-aromatic heterocyclicgroup, or

(4) an optionally substituted C₁₋₆ alkyl group;

R² is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a fluorine atom, a chlorine atom), or

(3) an optionally substituted C₁₋₆ alkyl group (e.g., methyl);

R³ is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) an optionally substituted C₁₋₆ alkyl group (e.g., methyl),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl);

R⁴ is

(1) a halogen atom,

(2) a cyano group,

(3) a C₁₋₆ alkyl group,

(4) an optionally substituted C₁₋₆ alkoxy group,

(5) an optionally substituted carbamoyl group, or

(6) an optionally substituted 5- or 6-membered monocyclic aromaticheterocyclic group;

Ring A is a 6-membered aromatic ring (e.g., a benzene ring, a pyridinering) optionally further substituted by 1 to 3 substituents, in additionto R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a C₁₋₆ alkoxy group (e.g., methoxy); and

-   -   the partial structure represented by the following formula:

in the formula (I) is a partial structure represented by the followingformula:

[Compound C-2]

Compound (I) wherein

R¹ is

(1) a phenyl group, a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) ora 5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g.,tetrahydropyranyl), each of which is optionally substituted by 1 to 3substituents selected from

(i) a halogen atom (e.g., a fluorine atom),

(ii) a cyano group, and

(iii) a hydroxy group, or

(2) a C₁₋₆ alkyl group (e.g., methyl, isobutyl) optionally substitutedby 1 to 3 substituents selected from

-   -   (i) a hydroxy group, and    -   (ii) a 3- to 14-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group) (e.g., tetrahydrofuryl);

R² is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom, a fluorine atom), or

(3) a C₁₋₆ alkyl group (e.g., methyl);

R³ is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl);

R⁴ is

(1) a halogen atom (e.g., a chlorine atom, a fluorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom),

(5) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl), or

(6) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, pyridyl, triazolyl) optionally substituted by 1 to 3 C₁₋₆alkyl groups (e.g., methyl); and

Ring A is a 6-membered aromatic ring (e.g., a benzene ring, a pyridinering) optionally further substituted by 1 to 3 substituents, in additionto R⁴, selected from

(1) a halogen atom (e.g., a fluorine atom), and

(2) a C₁₋₆ alkoxy group (e.g., methoxy).

[Compound Ca-2]

Compound (I) wherein

R¹ is

(1) a phenyl group, a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) ora 5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g.,tetrahydropyranyl), each of which is optionally substituted by 1 to 3substituents selected from

(i) a halogen atom (e.g., a fluorine atom),

(ii) a cyano group, and

(iii) a hydroxy group, or

(2) a C₁₋₆ alkyl group (e.g., methyl, isobutyl) optionally substitutedby 1 to 3 substituents selected from

-   -   (i) a hydroxy group, and    -   (ii) a 3- to 14-membered non-aromatic heterocyclic group        (preferably a 3- to 8-membered monocyclic non-aromatic        heterocyclic group) (e.g., tetrahydrofuryl);

R² is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom, a fluorine atom), or

(3) a C₁₋₆ alkyl group (e.g., methyl);

R³ is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl);

R⁴ is

(1) a halogen atom (e.g., a chlorine atom, a fluorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom),

(5) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl), or

(6) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, pyridyl, triazolyl) optionally substituted by 1 to 3 C₁₋₆alkyl groups (e.g., methyl);

Ring A is a 6-membered aromatic ring (e.g., a benzene ring, a pyridinering) optionally further substituted by 1 to 3 substituents, in additionto R⁴, selected from

(1) a halogen atom (e.g., a fluorine atom), and

(2) a C₁₋₆ alkoxy group (e.g., methoxy); and

-   -   the partial structure represented by the following formula:

in the formula (I) is a partial structure represented by the followingformula:

[Compound C-3]

Compound (I) wherein

R¹ is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(i) a halogen atom (e.g., a fluorine atom), and

(ii) a cyano group,

(2) a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) optionallysubstituted by 1 to 3 hydroxy groups,

(3) a 5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) optionally substituted by 1 to 3 hydroxy groups, or

(4) a C₁₋₆ alkyl group (e.g., methyl, isobutyl) optionally substitutedby 1 to 3 substituents selected from

-   -   (i) a hydroxy group, and    -   (ii) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydrofuryl);

R² is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom, a fluorine atom), or

(3) a C₁₋₆ alkyl group (e.g., methyl);

R³ is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl);

R⁴ is

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom),

(5) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl), or

(6) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, pyridyl, triazolyl) optionally substituted by 1 to 3 C₁₋₆alkyl groups (e.g., methyl); and

Ring A is a 6-membered aromatic ring (e.g., a benzene ring, a pyridinering) optionally further substituted by 1 to 3 substituents, in additionto R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a C₁₋₆ alkoxy group (e.g., methoxy).

[Compound Ca-3]

Compound (I) wherein

R¹ is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(i) a halogen atom (e.g., a fluorine atom), and

(ii) a cyano group,

(2) a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) optionallysubstituted by 1 to 3 hydroxy groups,

(3) a 5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) optionally substituted by 1 to 3 hydroxy groups, or

(4) a C₁₋₆ alkyl group (e.g., methyl, isobutyl) optionally substitutedby 1 to 3 substituents selected from

-   -   (i) a hydroxy group, and    -   (ii) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydrofuryl);

R² is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom, a fluorine atom), or

(3) a C₁₋₆ alkyl group (e.g., methyl);

R³ is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl);

R⁴ is

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom),

(5) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl), or

(6) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, pyridyl, triazolyl) optionally substituted by 1 to 3 C₁₋₆alkyl groups (e.g., methyl);

Ring A is a 6-membered aromatic ring (e.g., a benzene ring, a pyridinering) optionally further substituted by 1 to 3 substituents, in additionto R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a C₁₋₆ alkoxy group (e.g., methoxy); and

-   -   the partial structure represented by the following formula:

in the formula (I) is a partial structure represented by the followingformula:

[Compound C-4]

Compound (I) wherein

R¹ is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(i) a halogen atom (e.g., a fluorine atom), and

(ii) a cyano group,

(2) a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) optionallysubstituted by 1 to 3 hydroxy groups,

(3) a tetrahydropyranyl group optionally substituted by 1 to 3 hydroxygroups, or

(4) a C₁₋₆ alkyl group (e.g., methyl, isobutyl) optionally substitutedby 1 to 3 substituents selected from

(i) a hydroxy group, and

(ii) a tetrahydrofuryl group;

R² is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom, a fluorine atom), or

(3) a C₁₋₆ alkyl group (e.g., methyl);

R³ is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl);

R⁴ is

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom),

(5) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl),

(6) a pyrazolyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl),

(7) a pyridyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl), or

(8) a triazolyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl); and

Ring A is

(1) a benzene ring optionally further substituted by 1 to 3substituents, in addition to R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a C₁₋₆ alkoxy group (e.g., methoxy), or

(2) a pyridine ring.

[Compound Ca-4]

Compound (I) wherein

R¹ is

(1) a phenyl group optionally substituted by 1 to 3 substituentsselected from

(i) a halogen atom (e.g., a fluorine atom), and

(ii) a cyano group,

(2) a C₅₋₆ cycloalkyl group (cyclopentyl, cyclohexyl) optionallysubstituted by 1 to 3 hydroxy groups,

(3) a tetrahydropyranyl group optionally substituted by 1 to 3 hydroxygroups, or

(4) a C₁₋₆ alkyl group (e.g., methyl, isobutyl) optionally substitutedby 1 to 3 substituents selected from

(i) a hydroxy group, and

(ii) a tetrahydrofuryl group;

R² is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom, a fluorine atom), or

(3) a C₁₋₆ alkyl group (e.g., methyl);

R³ is

(1) a hydrogen atom,

(2) a halogen atom (e.g., a chlorine atom),

(3) a cyano group,

(4) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom),

(5) a C₁₋₆ alkoxy group (e.g., methoxy), or

(6) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl);

R⁴ is

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) a C₁₋₆ alkyl group (e.g., methyl),

(4) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted by 1 to 3halogen atoms (e.g., a fluorine atom),

(5) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., methylcarbamoyl),

(6) a pyrazolyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl),

(7) a pyridyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl), or

(8) a triazolyl group optionally substituted by 1 to 3 C₁₋₆ alkyl groups(e.g., methyl);

Ring A is

(1) a benzene ring optionally further substituted by 1 to 3substituents, in addition to R⁴, selected from

(a) a halogen atom (e.g., a fluorine atom), and

(b) a C₁₋₆ alkoxy group (e.g., methoxy), or

(2) a pyridine ring; and

the partial structure represented by the following formula:

in the formula (I) is a partial structure represented by the followingformula:

[Compound D-1]

Compound (I) wherein

R¹ is

(1) a C₅₋₆ cycloalkyl group (e.g., cyclohexyl) optionally substituted by1 to 3 hydroxy groups, or

(2) a 5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) optionally substituted by 1 to 3 hydroxy groups;

R² is

(1) a halogen atom (e.g., a fluorine atom), or

(2) a C₁₋₆ alkyl group (e.g., methyl);

R³ is a C₁₋₆ alkyl group (e.g., methyl);

R⁴ is

(1) a C₁₋₆ alkyl group (e.g., methyl),

(2) a C₁₋₆ alkoxy group (e.g., methoxy), or

(3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl); and

Ring A is a benzene ring or a pyridine ring, each of which isunsubstituted, in addition to R⁴.

[Compound Da-1]

Compound (I) wherein

R¹ is

(1) a C₅₋₆ cycloalkyl group (e.g., cyclohexyl) optionally substituted by1 to 3 hydroxy groups, or

(2) a 5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g.,tetrahydropyranyl) optionally substituted by 1 to 3 hydroxy groups;

R² is

(1) a halogen atom (e.g., a fluorine atom), or

(2) a C₁₋₆ alkyl group (e.g., methyl);

R³ is a C₁₋₆ alkyl group (e.g., methyl);

R⁴ is

(1) a C₁₋₆ alkyl group (e.g., methyl),

(2) a C₁₋₆ alkoxy group (e.g., methoxy), or

(3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl);

Ring A is a benzene ring or a pyridine ring, each of which isunsubstituted, in addition to R⁴; and

the partial structure represented by the following formula:

in the formula (I) is a partial structure represented by the followingformula:

[Compound D-2]

Compound (I) wherein

R¹ is

(1) a cyclohexyl group substituted by one hydroxy group, or

(2) a tetrahydropyranyl group substituted by one hydroxy group;

R² is

(1) a halogen atom (e.g., a fluorine atom), or

(2) a C₁₋₆ alkyl group (e.g., methyl);

R³ is a C₁₋₆ alkyl group (e.g., methyl);

R⁴ is

(1) a C₁₋₆ alkyl group (e.g., methyl),

(2) a C₁₋₆ alkoxy group (e.g., methoxy), or

(3) a pyrazolyl group; and

Ring A is a benzene ring or a pyridine ring, each of which isunsubstituted, in addition to R⁴.

[Compound Da-2]

Compound (I) wherein

R¹ is

(1) a cyclohexyl group substituted by one hydroxy group, or

(2) a tetrahydropyranyl group substituted by one hydroxy group;

R² is

(1) a halogen atom (e.g., a fluorine atom), or

(2) a C₁₋₆ alkyl group (e.g., methyl);

R³ is a C₁₋₆ alkyl group (e.g., methyl);

R⁴ is

(1) a C₁₋₆ alkyl group (e.g., methyl),

(2) a C₁₋₆ alkoxy group (e.g., methoxy), or

(3) a pyrazolyl group;

Ring A is a benzene ring or a pyridine ring, each of which isunsubstituted, in addition to R⁴; and

the partial structure represented by the following formula:

in the formula (I) is a partial structure represented by the followingformula:

[Compound E]

-   2-[(3S,4S)-4-Hydroxytetrahydro-2H-pyran-3-yl]-6-(4-methoxybenzyl)-4,5-dimethyl-2,3-dihydro-1H-isoindol-1-one,    or a salt thereof-   4-Fluoro-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindol-1-one,    or a salt thereof-   2-((1S,2S)-2-Hydroxycyclohexyl)-4,5-dimethyl-6-((6-methylpyridin-3-yl)methyl)isoindolin-1-one,    or a salt thereof

When compound (I) is in a form of a salt, examples of such salt includesalts with inorganic base, an ammonium salt, salts with organic base,salts with inorganic acid, salts with organic acid, salts with basic oracidic amino acid, and the like.

Preferable examples of the salt with inorganic base include alkali metalsalts such as sodium salt, potassium salt and the like; alkaline earthmetal salts such as calcium salt, magnesium salt, barium salt and thelike; an aluminum salt, and the like.

Preferable examples of the salt with organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine and the like.

Preferable examples of the salt with inorganic acid include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like.

Preferable examples of the salt with organic acid include salts withformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acidand the like.

Preferable examples of the salt with basic amino acid include salts witharginine, lysine, ornithine and the like.

Preferable examples of the salt with acidic amino acid include saltswith aspartic acid, glutamic acid and the like.

Among these salts, a pharmaceutically acceptable salt is preferable.When a compound has a basic functional group, preferable examples of thepharmaceutically acceptable salt include salts with inorganic acid suchas hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like, and salts with organic acid such as aceticacid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, methanesulfonic acid,p-toluenesulfonic acid and the like. In addition, when a compound has anacidic functional group, examples thereof include inorganic salts suchas alkali metal salts (e.g., sodium salt, potassium salt etc.), alkalineearth metal salts (e.g., calcium salt, magnesium salt, barium salt etc.)and the like, ammonium salt and the like.

Compound (I) may be a crystal, and both a single crystal and crystalmixtures are encompassed in the compound (I).

Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystalsalt. Here, the cocrystal or cocrystal salt means a crystallinesubstance consisting of two or more particular substances which aresolids at room temperature, each having different physical properties(e.g., structure, melting point, heat of melting, hygroscopicity,solubility, stability etc.). The cocrystal and cocrystal salt can beproduced by cocrystallization method known per se.

Compound (I) encompasses solvates (e.g., hydrate) and non-solvateswithin the scope thereof. Compound (I) may be a compound labeled orsubstituted with an isotope (e.g., ²H, ³H, ¹¹C, ¹⁴C, ¹⁸F, ³⁵S, ¹²⁵I). Acompound labeled with or substituted by an isotope can be used, forexample, as a tracer used for Positron Emission Tomography (PET) (PETtracer), and is useful in the field of medical diagnosis and the like.

When compound (I) of the present invention has an asymmetric center,isomers such as enantiomer, diastereomer and the like may be present.Such isomers and a mixture thereof are all encompassed within the scopeof the present invention. When an isomer is formed due to theconformation or tautomerism, such isomers and a mixture thereof are allencompassed in compound (I) of the present invention.

The production methods of the compound of the present invention areexplained below.

The raw material compound and reagent used and the compound obtained ineach step in the following production method may be each in a form of asalt, and examples of such salt include those similar to the salts ofthe compound of the present invention and the like.

When the compound obtained in each step is a free form, it can beconverted to the objective salt according to a method known per se. Whenthe compound obtained in each step is a salt, it can be converted to theobjective free form or the other salt according to a method known perse.

The compound obtained in each step can be used directly as the reactionmixture or as a crude product for the next reaction. Alternatively, thecompound obtained in each step can be isolated and purified from areaction mixture according to a method known per se, for example, aseparation means such as concentration, crystallization,recrystallization, distillation, solvent extraction, fractionaldistillation, column chromatography and the like.

When the raw material compound and reagent used in each step arecommercially available, the commercially available product can also beused directly.

In the reaction in each step, while the reaction time varies dependingon the kind of the reagent and solvent to be used, it is generally 1min-48 hr, preferably 10 min-8 hr, unless otherwise specified.

In the reaction in each step, while the reaction temperature variesdepending on the kind of the reagent and solvent to be used, it isgenerally −78° C.-300° C., preferably −78° C.-150° C., unless otherwisespecified.

In the reaction in each step, while the pressure varies depending on thekind of the reagent and solvent to be used, it is generally 1 atm-20atm, preferably 1 atm-3 atm, unless otherwise specified.

Microwave synthesizer such as Initiator manufactured by Biotage and thelike may be used for the reaction in each step. While the reactiontemperature varies depending on the kind of the reagent and solvent tobe used, it is generally room temperature-300° C., preferably 50°C.-250° C., unless otherwise specified. While the reaction time variesdepending on the kind of the reagent and solvent to be used, it isgenerally 1 min-48 hr, preferably 1 min-8 hr, unless otherwisespecified.

In the reaction in each step, the reagent is used in an amount of 0.5equivalents-20 equivalents, preferably 0.8 equivalents-5 equivalents,relative to the substrate, unless otherwise specified. When the reagentis used as a catalyst, the reagent is used in an amount of 0.001equivalents-1 equivalents, preferably 0.01 equivalents-0.2 equivalents,relative to the substrate. When the reagent is used as a reactionsolvent, the reagent is used in a solvent amount.

Unless otherwise specified, the reaction in each step is carried outwithout solvent, or by dissolving or suspending the raw materialcompound in a suitable solvent. Examples of the solvent include thosedescribed in Examples and the following solvents.

alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol andthe like;

ethers: diethyl ether, diphenyl ether, tetrahydrofuran,1,2-dimethoxyethane and the like;

aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;

saturated hydrocarbons: cyclohexane, hexane and the like; amides:N,N-dimethylformamide, N-methylpyrrolidone and the like;

halogenated hydrocarbons: dichloromethane, carbon tetrachloride and thelike;

nitriles: acetonitrile and the like;

sulfoxides: dimethyl sulfoxide and the like;

aromatic organic bases: pyridine and the like;

anhydrides: acetic anhydride and the like;

organic acids: formic acid, acetic acid, trifluoroacetic acid and thelike;

inorganic acids: hydrochloric acid, sulfuric acid and the like;

esters: ethyl acetate and the like;

ketones: acetone, methyl ethyl ketone and the like;

water.

The above-mentioned solvent can be used in a mixture of two or morekinds thereof in an appropriate ratio.

When a base is used for the reaction in each step, examples thereofinclude those described in Examples and the following bases.

inorganic bases: sodium hydroxide, magnesium hydroxide and the like;

basic salts: sodium carbonate, calcium carbonate, sodium hydrogencarbonate and the like;

organic bases: triethylamine, diethylamine, pyridine,4-dimethylaminopyridine, N,N-dimethylaniline,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,imidazole, piperidine and the like;

metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like;

alkali metal hydrides: sodium hydride and the like;

metal amides: sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide and the like;

organic lithiums: n-butyllithium and the like.

When an acid or an acid catalyst is used for the reaction in each step,examples thereof include those described in Examples and the followingacids and acid catalysts.

inorganic acids: hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, phosphoric acid and the like;

organic acids: acetic acid, trifluoroacetic acid, citric acid,p-toluenesulfonic acid, 10-camphorsulfonic acid and the like;

Lewis acid: boron trifluoride diethyl ether complex, zinc iodide,anhydrous aluminium chloride, anhydrous zinc chloride, anhydrous ironchloride and the like.

Unless otherwise specified, the reaction in each step is carried outaccording to a method known per se, for example, the method described inJikken Kagaku Kouza, 5th Edition, vol. 13-19 (the Chemical Society ofJapan ed.); Shin Jikken Kagaku Kouza, vol. 14-15 (the Chemical Societyof Japan ed.); Fine Organic Chemistry, Revised 2nd Edition (L. F.Tietze, Th. Eicher, Nankodo); Organic Name Reactions, the ReactionMechanism and Essence, Revised Edition (Hideo Togo, Kodansha); ORGANICSYNTHESES Collective Volume I-VII (John Wiley & Sons Inc); ModernOrganic Synthesis in the Laboratory A Collection of StandardExperimental Procedures (Jie Jack Li, OXFORD UNIVERSITY); ComprehensiveHeterocyclic Chemistry III, Vol. 1-Vol. 14 (Elsevier Japan); StrategicApplications of Named Reactions in Organic Synthesis (translated byKiyoshi Tomioka, Kagakudojin); Comprehensive Organic Transformations(VCH Publishers Inc.), 1989, or the like, or the method described inExamples.

In each step, protection or deprotection of functional groups isperformed according to a method known per se, for example, the methodsdescribed in Wiley-Interscience, 2007, “Protective Groups in OrganicSynthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts); Thieme,2004, “Protecting Groups 3rd Ed.” (P. J. Kocienski) and the like, or themethods described in the Examples.

Examples of the protecting group for hydroxyl group of alcohol and thelike and phenolic hydroxyl group include ether-type protecting groupssuch as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether,tetrahydropyranyl ether and the like; carboxylate-type protecting groupssuch as acetate and the like; sulfonate-type protecting groups such asmethanesulfonate and the like; carbonate-type protecting groups such ast-butyl carbonate and the like; and the like.

Examples of the protecting group for carbonyl group of aldehyde includeacetal-type protecting groups such as dimethyl acetal and the like;cyclic acetal-type protecting groups such as cyclic 1,3-dioxane and thelike; and the like.

Examples of the protecting group for carbonyl group of ketone includeketal-type protecting groups such as dimethyl ketal and the like; cyclicketal-type protecting groups such as cyclic 1,3-dioxane and the like;oxime-type protecting groups such as O-methyloxime and the like;hydrazone-type protecting groups such as N,N-dimethylhydrazone and thelike; and the like.

Examples of the protecting group for carboxyl group include ester-typeprotecting groups such as methyl ester and the like; amide-typeprotecting groups such as N,N-dimethylamide and the like; and the like.

Examples of the protecting group for thiol include ether-type protectinggroups such as benzyl thioether and the like; ester-type protectinggroups such as thioacetate, thiocarbonate, thiocarbamate and the like;and the like.

Examples of the protecting group for amino group, and aromaticheterocycle such as imidazole, pyrrole, indole and the like includecarbamate-type protecting groups such as benzyl carbamate, tert-butylcarbamate and the like; amide-type protecting groups such as acetamideand the like; alkylamine-type protecting groups such asN-triphenylmethylamine and the like; sulfonamide-type protecting groupssuch as methanesulfonamide and the like; and the like.

Protecting groups can be removed by a method known per se, for example,methods using acid, base, ultraviolet rays, hydrazine, phenylhydrazine,sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladiumacetate, trialkylsilyl halide (e.g., trimethylsilyl iodide,trimethylsilyl bromide), reduction methods and the like.

When reduction reaction is carried out in each step, examples of thereducing agent to be used include metal hydrides such as lithiumaluminium hydride, sodium triacetoxyborohydride, sodiumcyanoborohydride, diisobutylaluminium hydride (DIBAL-H), sodiumborohydride, tetramethylammonium triacetoxyborohydride and the like;boranes such as borane tetrahydrofuran complex and the like; Raneynickel; Raney cobalt; hydrogen; formic acid; triethylsilane and thelike. When carbon-carbon double bond or triple bond is reduced, a methodusing a catalyst such as palladium-carbon, Lindlar's catalyst and thelike may be employed.

When oxidation reaction is carried out in each step, examples of theoxidizing agent to be used include peroxides such as m-chloroperbenzoicacid (mCPBA), hydrogen peroxide, t-butylhydroperoxide and the like;perchlorates such as tetrabutylammonium perchlorate and the like;chlorates such as sodium chlorate and the like; chlorites such as sodiumchlorite and the like; periodic acids such as sodium periodate and thelike; hypervalent iodine reagents such as iodosylbenzene and the like;reagents containing manganese such as manganese dioxide, potassiumpermanganate and the like; leads such as lead tetraacetate and the like;reagents containing chromium such as pyridinium chlorochromate (PCC),pyridinium dichromate (PDC), Jones reagent and the like; halogencompounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone;sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide;2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

When radical cyclization reaction is carried out in each step, examplesof the radical initiator to be used include azo compounds such asazobisisobutyronitrile (AIBN) and the like; water-soluble radicalinitiators such as 4-4′-azobis-4-cyanopentanoic acid (ACPA) and thelike; triethylboron in the presence of air or oxygen; benzoyl peroxideand the like. Examples of the radical reagent to be used includetributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane,diphenylsilane, samarium iodide and the like.

When Wittig reaction is carried out in each step, examples of the Wittigreagent to be used include alkylidene phosphoranes and the like. Thealkylidene phosphoranes can be prepared according to a method known perse, for example, by reacting a phosphonium salt with a strong base.

When Horner-Emmons reaction is carried out in each step, examples of thereagent to be used include phosphonoacetates such as methyldimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like;and bases such as alkali metal hydrides, organic lithiums and the like.

When Friedel-Crafts reaction is carried out in each step, a combinationof a Lewis acid and an acid chloride or a combination of a Lewis acidand an alkylating agent (e.g., an alkyl halide, an alcohol, an olefinetc.) is used as a reagent. Alternatively, an organic acid or aninorganic acid can also be used instead of a Lewis acid, and ananhydride such as acetic anhydride and the like can also be used insteadof an acid chloride.

When aromatic nucleophilic substitution reaction is carried out in eachstep, a nucleophile (e.g., an amine, imidazole etc.) and a base (e.g., abasic salt, an organic base etc.) are used as a reagent.

When nucleophilic addition reaction by a carbo anion, nucleophilic1,4-addition reaction (Michael addition reaction) by a carbo anion ornucleophilic displacement reaction by a carbo anion is carried out ineach step, examples of the base to be used for generation of the carboanion include organic lithiums, metal alkoxides, inorganic bases,organic bases and the like.

When Grignard reagent is carried out in each step, examples of theGrignard reagent to be used include arylmagnesium halides such asphenylmagnesium bromide and the like; and alkylmagnesium halides such asmethylmagnesium bromide and the like. The Grignard reagent can beprepared according to a method known per se, for example, by reacting analkyl halide or an aryl halide with a metal magnesium in an ether ortetrahydrofuran as a solvent.

When Knoevenagel condensation reaction is carried out in each step, acompound having an activated methylene group with two electronwithdrawing groups (e.g., malonic acid, diethyl malonate, malononitrileetc.) and a base (e.g., an organic base, a metal alkoxide, an inorganicbase) are used as a reagent.

When Vilsmeier-Haack reaction is carried out in each step, phosphorylchloride and an amide derivative (e.g., N,N-dimethylformamide etc.) areused as a reagent.

When azidation reaction of an alcohol, an alkyl halide or a sulfonate iscarried out in each step, examples of the azidating agent to be usedinclude diphenylphosphorylazide (DPPA), trimethylsilylazide, sodiumazide and the like. For example, for the azidation reaction of analcohol, a method using diphenylphosphorylazide and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), a method usingtrimethylsilylazide and a Lewis acid, and the like are employed.

When reductive amination reaction is carried out in each step, examplesof the reducing agent to be used include sodium triacetoxyborohydride,sodium cyanoborohydride, hydrogen, formic acid and the like. When thesubstrate is an amine compound, examples of the carbonyl compound to beused include paraformaldehyde, aldehydes such as acetaldehyde and thelike, and ketones such as cyclohexanone and the like. When the substrateis a carbonyl compound, examples of the amine to be used includeammonia, primary amines such as methylamine and the like; secondaryamines such as dimethylamine and the like, and the like.

When Mitsunobu reaction is carried out in each step, an azodicarboxylate(e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate(DIAD) etc.) and triphenylphosphine are used as a reagent.

When esterification reaction, amidation reaction or ureation reaction iscarried out in each step, examples of the reagent to be used includeacyl halides such as acid chlorides, acid bromides and the like;activated carboxylic acids such as anhydrides, activated esters,sulfates and the like. Examples of the activating agent of thecarboxylic acid include carbodiimide condensing agents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) andthe like; triazine condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloriden-hydrate (DMT-MM) and the like; carbonate condensing agents such as1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphoryl azide(DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOPreagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent);thionyl chloride; lower alkyl haloformates such as ethyl chloroformateand the like; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphorate (HATU); sulfuric acid; combinations thereof andthe like. When carbodiimide condensing agent is used, an additive suchas 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP) and the like may be added to the reactionsystem.

When coupling reaction is carried out in each step, examples of themetal catalyst to be used include palladium compounds such aspalladium(II) acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride,palladium(II) acetate and the like; nickel compounds such astetrakis(triphenylphosphine)nickel(0) and the like; rhodium compoundssuch as tris(triphenylphosphine)rhodium(III) chloride and the like;cobalt compounds; copper compounds such as copper oxide, copper(I)iodide and the like; platinum compounds and the like. In addition, abase can be added to the reaction system, and examples thereof includeinorganic bases, basic salts and the like.

When thiocarbonylation reaction is carried out in each step, phosphoruspentasulfide is typically used as the thiocarbonylating agent.Alternatively, a reagent having a1,3,2,4-dithiadiphosphetane-2,4-disulfide structure (e.g.,2,4-bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lawesson reagent) etc.) can also be used instead of phosphoruspentasulfide.

When Wohl-Ziegler reaction is carried out in each step, examples of thehalogenating agent to be used include N-iodosuccinimide,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfurylchloride and the like. In addition, the reaction can be accelerated bysubjecting a radical initiator such as heat, light, benzoyl peroxide,azobisisobutyronitrile and the like to the reaction system reaction.

When halogenation reaction of a hydroxy group is carried out in eachstep, examples of the halogenating agent to be used include hydrohalicacids and acid halides of inorganic acids, specifically, hydrochloricacid, thionyl chloride, phosphorus oxychloride and the like forchlorination, 48% hydrobromic acid and the like for bromination. Inaddition, a method of producing an alkyl halide by reacting an alcoholwith triphenylphosphine and carbon tetrachloride or carbon tetrabromideor the like can be employed. Alternatively, a method of producing analkyl halide via two step comprising converting an alcohol to thecorresponding sulfonate, and then reacting the sulfonate with lithiumbromide, lithium chloride or sodium iodide can also be employed.

When Arbuzov reaction is carried out in each step, examples of thereagent to be used include alkyl halides such as ethyl bromoacetate andthe like; and phosphites such as triethyl phosphite,tri(isopropyl)phosphite and the like.

When sulfonate esterification reaction is carried out in each step,examples of the sulfonating agent to be used include methanesulfonylchloride, p-toluenesulfonyl chloride, methanesulfonic anhydride,p-toluenesulfonic anhydride, N-phenylbis(trifluoromethanesulfonimide)and the like.

When hydrolysis reaction is carried out in each step, an acid or a baseis used as a reagent. For acid hydrolysis reaction of t-butyl ester,formic acid, triethylsilane and the like may be added toreductively-trap t-butyl cation which is by-produced.

When dehydration reaction is carried out in each step, examples of thedehydrating agent to be used include sulfuric acid, diphosphoruspentaoxide, phosphorus oxychloride, N,N′-dicyclohexylcarbodiimide,alumina, polyphosphoric acid and the like.

Compound (I) can be produced from compound (1) or compound (2) accordingto the following method.

wherein X¹ is a C₁₋₆ alkyl group (e.g., methyl, ethyl), X² is a halogenatom (e.g., a fluorine atom), and the other symbols are as definedabove.

In Scheme (a), compound (3) can be produced by subjecting compound (1)to an oxidation reaction using an oxidant containing manganese such aspotassium permanganate and the like, or subjecting compound (2) to ahydrolysis reaction.

Compound (4) can be produced by esterification reaction between compound(3) and alcohols under the acidic conditions with sulfuric acid.

Compound (5) can be produced by subjecting compound (4) to ahalogenation reaction using a halogenating agent such as bromine and thelike.

Compound (6) can be produced by subjecting compound (5) to a couplingreaction in the presence of a metal catalyst. The reaction may be a twostep-reaction via a borate. The halide to be reacted with a borate canbe produced according to a method known per se.

Compound (7) can be produced by subjecting compound (6) to a sulfonateesterification reaction using a sulfonating agent.

Compound (8) can be produced by subjecting compound (7) to a couplingreaction in the presence of a palladium compound.

Compound (9) can be produced by subjecting compound (8) to an oxidationreaction.

Compound (I) can be produced by subjecting compound (9) to a reductiveamination reaction with an amine using a reducing agent.

Compound (I) can also be produced from compound (6) according to thefollowing method.

wherein each symbol is as defined above.

In Scheme (b), compound (10) can be produced by subjecting compound (6)to a hydrolysis reaction using an acid or a base.

Compound (11) can be produced by activating compound (10) using anactivating agent of a carboxylic acid, and then subjecting the resultingcompound to an amidation reaction with an amine.

Compound (12) can be produced by subjecting compound (11) to a sulfonateesterification reaction using a sulfonating agent.

Compound (13) can be produced by subjecting compound (12) to a couplingreaction in the presence of a palladium compound.

Compound (14) can be produced by subjecting compound (13) to anoxidation reaction. In the reaction, the resulting aldehyde is cyclized.Examples of the oxidant to be used include those similar to the oxidantused in the step of producing compound (9) from compound (8) in Scheme(a).

Compound (I) can be produced by subjecting compound (14) to a reductionreaction.

When compound (I) has an optical isomer, a stereoisomer, a regioisomeror a rotamer, these are also encompassed in compound (I), and can beobtained as a single product according to synthesis and separationmethods known per se. For example, when compound (I) contains an opticalisomer, an optical isomer resolved from this compound is alsoencompassed in compound (I).

The optical isomer can be produced according to a method known per se.To be specific, the optical isomer is obtained using an optically activesynthetic intermediate, or subjecting the final racemate product to anoptical resolution according to a conventional method.

For example, the method of optical resolution may be a method known perse, such as a fractional recrystallization method, a chiral columnmethod, a diastereomer method etc.

1) Fractional Recrystallization Method

A method wherein a salt with a racemate with an optically activecompound (e.g., (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid,(−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine,cinchonine, (−)-cinchonidine, brucine etc.) is formed, which isseparated by a fractional recrystallization method, and if desired, aneutralization step to give a free optical isomer.

2) Chiral Column Method

A method wherein a racemate or a salt thereof is applied to a column forseparation of an optical isomer (a chiral column) to allow separation.In the case of a liquid chromatography, for example, a mixture of theoptical isomers is applied to a chiral column such as ENANTIO-OVM(manufactured by Tosoh Corporation), CHIRAL series (manufactured byDaicel Corporation) and the like, and developed with water, variousbuffers (e.g., phosphate buffer, etc.) and organic solvents (e.g.,ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid,diethylamine etc.), solely or as a mixed solution thereof to separatethe optical isomer.

3) Diastereomer Method

A method wherein a racemic mixture is prepared into a diastereomericmixture by chemical reaction with an optically active reagent, which ismade into a single substance by a typical separation means (e.g., afractional recrystallization method, a chromatography method etc.) andthe like, and is subjected to a chemical treatment such as hydrolysisand the like to remove an optically active reagent moiety, whereby anoptical isomer is obtained. For example, when compound (I) containshydroxy group, or primary or secondary amino group within a molecule,the compound and an optically active organic acid (e.g., MTPA[α-methoxy-α-(trifluoromethyl)phenylacetic acid], (−)-menthoxyaceticacid etc.) and the like are subjected to condensation reaction to givediastereomers of the ester compound or the amide compound, respectively.When compound (I) has a carboxylic acid group, this compound and anoptically active amine or an optically active alcohol reagent aresubjected to condensation reaction to give diastereomers of the amidecompound or the ester compound, respectively. The separated diastereomeris converted to an optical isomer of the original compound by acidhydrolysis or base hydrolysis.

When compound (I) is obtained as a free compound, the compound can beconverted to an objective salt according to a method known per se or amethod analogous thereto. Conversely, when it is obtained in the form ofa salt, the salt can be converted to a free form or other objective saltaccording to a method known per se or a method analogous thereto.

Compound (I) may be a prodrug, and the prodrug of compound (I) refers toa compound which is converted to compound (I) as a result of a reactionwith an enzyme, gastric acid, etc. under physiological conditions invivo, thus a compound that undergoes enzymatic oxidation, reduction,hydrolysis etc. to convert to compound (I) and a compound that undergoeshydrolysis and the like by gastric acid, etc. to convert to compound(I).

Examples of the prodrug for compound (I) include a compound obtained bysubjecting an amino group in compound (I) to acylation, alkylation orphosphorylation (e.g., a compound obtained by subjecting an amino groupin compound (I) to eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofurylation, pyrrolidylmethylation, pivaloyloxymethylation ort-butylation, and the like); a compound obtained by subjecting a hydroxygroup in compound (I) to acylation, alkylation, phosphorylation orboration (e.g., a compound obtained by subjecting a hydroxy group incompound (I) to acetylation, palmitoylation, propanoylation,pivaloylation, succinylation, fumarylation, alanylation ordimethylaminomethylcarbonylation, and the like); a compound obtained bysubjecting a carboxyl group in compound (I) to esterification oramidation (e.g., a compound obtained by subjecting a carboxyl group incompound (I) to ethyl esterification, phenyl esterification,carboxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethyl esterification ormethylamidation, and the like) and the like. Any of these compounds canbe produced from compound (I) according to a method known per se.

A prodrug of compound (I) may also be one which is converted to compound(I) under physiological conditions as described in “IYAKUHIN no KAIHATSU(Development of Pharmaceuticals)”, Vol. 7, Design of Molecules, p.163-198 (HIROKAWA SHOTEN).

Compound (I) may be a crystal, and a single crystal form and a mixtureof crystal forms are both encompassed in compound (I) of the presentinvention. The crystal can be produced by crystallizing according to acrystallization method known per se.

Compound (I) is useful for mammals (e.g., mouse, rat, hamster, rabbit,cat, dog, bovine, sheep, monkey, human etc.) as an agent for theprophylaxis or treatment of diseases, for example,

(1) psychiatric diseases (e.g., depression, major depression, bipolardepression, dysthymic disorder, emotional disorder (seasonal affectivedisorder and the like), recurrent depression, postpartum depression,stress disorder, depression symptom, mania, anxiety, generalized anxietydisorder, anxiety syndrome, panic disorder, phobia, social phobia,social anxiety disorder, obsessive disorder, post-traumatic stresssyndrome, post-traumatic stress disorder, Tourette syndrome, autism,autism spectrum syndrome, fragile X syndrome, Rett syndrome, adjustmentdisorder, bipolar disorder, neurosis, schizophrenia (e.g., positivesymptom, negative symptom, and cognitive impairment), cognitiveimpairment associated with schizophrenia, chronic fatigue syndrome,anxiety neurosis, compulsive neurosis, epilepsy, anxiety symptom,anxious mental state, emotional abnormality, cyclothymia, nervouserethism, faint, addiction, low sex drive, attention deficithyperactivity disorder (ADHD), psychotic major depression, refractorymajor depression, treatment-resistant depression],(2) neurodegenerative diseases [e.g., Alzheimer's disease,Alzheimer-type senile dementia, Parkinson's disease, Parkinson's diseasedementia, Huntington's disease, multi-infarct dementia, frontotemporaldementia, frontotemporal dementia Parkinson's Type, progressivesupranuclear palsy, Pick's syndrome, Niemann-Pick syndrome, corticobasaldegeneration, Down's syndrome, vascular dementia, postencephaliticparkinsonism, dementia with Lewy bodies, HIV dementia, amyotrophiclateral sclerosis (ALS), motor neurogenesis disease (MND),Creutzfeldt-Jakob disease or prion disease, cerebral palsy, multiplesclerosis],(3) age-related cognition and memory disorders [e.g., age-related memorydisorders, senile dementia](4) sleep disorders [e.g., intrinsic sleep disorders (e.g.,psychophysiological insomnia and the like), extrinsic sleep disorder,circadian rhythm disorders (e.g., time zone change syndrome (jet lag),shift work sleep disorder, irregular sleep-wake pattern, delayed sleepphase syndrome, advanced sleep phase syndrome, non-24-hour sleep-wakeand the like), parasomnia, sleep disorders associated with internalmedical or psychiatric disorder (e.g., chronic obstructive pulmonarydiseases, Alzheimer's disease, Parkinson's disease, cerebrovasculardementia, schizophrenia, depression, anxiety neurosis), stress insomnia,insomnia, insomniac neurosis, sleep apnea syndrome],(5) respiratory depression caused by anesthetics, traumatic disease, orneurodegenerative disease and the like,(6) traumatic brain injury, cerebral apoplexy, neurotic anorexia, eatingdisorder, anorexia nervosa, hyperorexia, other eating disorder, alcoholdependence, alcohol abuse, alcoholic amnesia, alcohol paranoia, alcoholpreference, alcohol withdrawal, alcoholic insanity, alcohol poisoning,alcoholic jealousy, alcoholic mania, alcohol-dependent psychiatricdisorder, alcoholic insanity, pharmacophilia, pharmacophobia,pharmacomania, drug withdrawal, migraine, stress headache, catatonicheadache, diabetic neuropathy, obesity, diabetes, muscular spasm,Meniere's disease, autonomic ataxia, alopecia, glaucoma, hypertension,cardiac disease, tachycardia, congestive cardiac failure,hyperventilation, bronchial asthma, apnea, sudden infant death syndrome,inflammatory disease, allergic disease, impotence, climacteric disorder,infertility, cancer, immunodeficiency syndrome caused by HIV infection,immunodeficiency syndrome caused by stress, cerebrospinal meningitis,acromegaly, incontinence, metabolic syndrome, osteoporosis, pepticulcer, irritable bowel syndrome, inflammatory bowel disease, ulcerativecolitis, Crohn's disease, stress gastrointestinal disorder, nerologicalvomiting, peptic ulcer, diarrhea, constipation, postoperative ileus,stress gastrointestinal disorder, and(7) pain.A cholinergic muscarinic M1 receptor positive allosteric modulator isparticularly preferably useful for the prophylaxis or treatment ofAlzheimer's disease, schizophrenia, pain, sleep disorder, Parkinson'sdisease dementia, dementia with Lewy bodies and the like.

Since compound (I) has a high cholinergic muscarinic M1 receptorpositive allosteric modulator activity, it is expected to provide anexcellent prophylactic or therapeutic effect for the above-mentioneddiseases.

Compound (I) shows excellent solubility in water, the second solution ofJapanese Pharmacopeia Elution Test, or the second solution of JapanesePharmacopoeia Disintegration Test, shows excellent in vivo kinetics(e.g., plasma drug half-life, intracerebral migration, metabolicstability, CYP inhibition), shows low toxicity (e.g., more excellent asa medicament in terms of acute toxicity, chronic toxicity, genetictoxicity, reproductive toxicity, cardiotoxicity, drug interaction,carcinogenicity, phototoxicity, and the like), and also has excellentproperties as a pharmaceutical product such as a few side effects.Therefore, compound (I) can be safely administered orally orparenterally to a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog,bovine, sheep, monkey, human and the like). Examples of the “parenteral”include intravenous, intramuscular, subcutaneous, intra-organ,intranasal, intradermal, instillation, intracerebral, intrarectal,intravaginal, intraperitoneal and intratumor administrations,administration to the vicinity of tumor etc. and direct administrationto the lesion.

A preparation containing compound (I) may be any of a solid preparationsuch as powder, granule, tablet, capsule, orally disintegrable film andthe like, or a liquid agent such as syrup, emulsion, injection and thelike.

The medicament of the present invention can be produced by aconventional method such as blending, kneading, granulation, tableting,coating, sterilization treatment, emulsification and the like accordingto the form of the preparation. As for the production of thepreparation, for example, each item of the Japanese PharmacopoeiaPreparation General Rules and the like can be referred to. In addition,the medicament of the present invention may be formed into asustained-release preparation containing an active ingredient and abiodegradable polymer compound. The sustained-release preparation can beproduced according to the method described in JP-A-H9-263545.

In the preparation of the present invention, the content of compound (I)varies depending on the form of the preparation, but is generally 0.01to 100% by weight, preferably 0.1 to 50% by weight, more preferably 0.5to 20% by weight, as the amount of compound (I) relative to the wholepreparation.

When compound (I) is used as the above-mentioned pharmaceuticalproducts, it may be used alone or in admixture with a suitable,pharmacologically acceptable carrier, for example, excipients (e.g.,starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.),binders (e.g., starch, arabic gum, carboxymethyl cellulose,hydroxypropyl cellulose, crystalline cellulose, alginic acid, gelatin,polyvinylpyrrolidone, etc.), lubricants (e.g., stearic acid, magnesiumstearate, calcium stearate, talc, etc.), disintegrants (e.g., calciumcarboxymethylcellulose, talc, etc.), diluents (e.g., water forinjection, physiological saline, etc.) and if desired, with theadditives (e.g., a stabilizer, a preservative, a colorant, a fragrance,a solubilizing agent, an emulsifier, a buffer, an isotonic agent, etc.)and the like, by a conventional method, which is processed into a dosageform of a solid agent such as powder, fine granule, granule, tablet,capsule and the like or a liquid form such as injection and the like,and safely administered orally or parenterally. When compound (I) isformed as a preparation for topical administration, it can also bedirectly administered to the affected part of an articular disease. Inthis case, an injection is preferable. The compound can also beadministered as a parenteral agent for topical administration (e.g.,intramuscular injection, subcutaneous injection, organ injection,injection to the vicinity of a joint and the like, solid preparationsuch as implant, granule, powder and the like, liquid such as suspensionand the like, ointment etc.) and the like.

For formulation into an injection, for example, compound (I) isformulated into an aqueous suspension with a dispersing agent (e.g.,surfactant such as Tween 80, HCO-60 and the like, polysaccharides suchas carboxymethylcellulose, sodium alginate, hyaluronic acid and thelike, polysorbate etc.), preservative (e.g., methylparaben,propylparaben etc.), isotonic agent (e.g., sodium chloride, mannitol,sorbitol, glucose etc.), buffer (e.g., calcium carbonate etc.), pHadjuster (e.g., sodium phosphate, potassium phosphate etc.) and the liketo give a practical preparation for injection. In addition, an oilysuspension can be obtained by dispersing the compound together withvegetable oil such as sesame oil, corn oil and the like or a mixturethereof with a phospholipid such as lecithin and the like, ormedium-chain triglyceride (e.g., miglyol 812 etc.) to give an injectionto be actually used.

The dose of compound (I) varies depending on the subject ofadministration, administration route and symptoms and is notparticularly limited. For example, for oral administration to adultpatients (body weight adult 40 to 80 kg, for example, 60 kg) withAlzheimer's disease, the dose is, for example, 0.001 to 1000 mg/kg bodyweight/day, preferably 0.01 to 100 mg/kg body weight/day, morepreferably 0.1 to 10 mg/kg body weight/day, as compound (I). This amountcan be administered in one to three portions per day.

A medicament containing the compound of the present invention can besafely administered solely or by mixing with a pharmaceuticallyacceptable carrier according to a method known per se (e.g., the methoddescribed in the Japanese Pharmacopoeia etc.) as the production methodof a pharmaceutical preparation, and in the form of, for example, tablet(including sugar-coated tablet, film-coated tablet, sublingual tablet,orally disintegrating tablet, buccal and the like), pill, powder,granule, capsule (including soft capsule, microcapsule), troche, syrup,liquid, emulsion, suspension, release control preparation (e.g.,immediate-release preparation, sustained-release preparation,sustained-release microcapsule), aerosol, film (e.g., orallydisintegrating film, oral mucosa-adhesive film), injection (e.g.,subcutaneous injection, intravenous injection, intramuscular injection,intraperitoneal injection), drip infusion, transdermal absorption typepreparation, ointment, lotion, adhesive preparation, suppository (e.g.,rectal suppository, vaginal suppository), pellet, nasal preparation,pulmonary preparation (inhalant), eye drop and the like, orally orparenterally (e.g., intravenous, intramuscular, subcutaneous,intraorgan, intranasal, intradermal, instillation, intracerebral,intrarectal, intravaginal, intraperitoneal administrations, andadministration to the lesion).

As the aforementioned “pharmaceutically acceptable carrier”, variousorganic or inorganic carriers conventionally used as preparationmaterials (starting materials) can be used. For example, excipient,lubricant, binder, disintegrant and the like are used for solidpreparations, and solvent, solubilizing agent, suspending agent,isotonic agent, buffer, soothing agent and the like are used for liquidpreparations. Where necessary, preparation additives such aspreservative, antioxidant, colorant, sweetening agent and the like canalso be used.

Examples of the excipient include lactose, sucrose, D-mannitol, starch,corn starch, crystalline cellulose, light anhydrous silicic acid and thelike.

Examples of the lubricant include magnesium stearate, calcium stearate,talc, colloidal silica and the like.

Examples of the binder include crystalline cellulose, white sugar,D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose,gelatin, methylcellulose, carboxymethylcellulose sodium and the like.

Examples of the disintegrant include starch, carboxymethylcellulose,carboxymethylcellulose calcium, sodium carboxymethyl starch,L-hydroxypropylcellulose and the like.

Examples of the solvent include water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the solubilizing agent include polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like.

Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzetonium chloride, glycerinmonostearate and the like; hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like; and the like.

Examples of the isotonic agent include glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol and the like.

Examples of the buffer include buffer solutions such as phosphates,acetates, carbonates, citrates and the like.

Examples of the soothing agent include benzyl alcohol and the like.

Examples of the preservative include p-oxybenzoates, chlorobutanol,benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid andthe like.

Examples of the antioxidant include sulfite, ascorbic acid, α-tocopheroland the like.

While the pharmaceutical composition varies according to the dosageform, administration method, carrier and the like, it can be producedaccording to a conventional method by adding the compound of the presentinvention in a proportion of generally 0.01-100%(w/w), preferably0.1-95%(w/w), of the total amount of the preparation.

The compound of the present invention can be used in combination withother active ingredients (hereinafter to be abbreviated as concomitantdrug).

Examples of the concomitant drug include the following. benzodiazepine(chlordiazepoxide, diazepam, potassium clorazepate, lorazepam,clonazepam, alprazolam etc.), L-type calcium channel inhibitor(pregabalin etc.), tricyclic or tetracyclic antidepressant (imipraminehydrochloride, amitriptyline hydrochloride, desipramine hydrochloride,clomipramine hydrochloride etc.), selective serotonin reuptake inhibitor(fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide,sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalateetc.), serotonin-noradrenaline reuptake inhibitor (venlafaxinehydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochlorideetc.), noradrenaline reuptake inhibitor (reboxetine mesylate etc.),noradrenaline-dopamine reuptake inhibitor (bupropion hydrochlorideetc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride,bupropion hydrochloride, setiptiline maleate, 5-HT_(1A) agonist(buspirone hydrochloride, tandospirone citrate, osemozotan hydrochlorideetc.), 5-HT₃ antagonist (cyamemazine etc.), heart non-selective βinhibitor (propranolol hydrochloride, oxprenolol hydrochloride etc.),histamine H₁ antagonist (hydroxyzine hydrochloride etc.), therapeuticdrug for schizophrenia (chlorpromazine, haloperidol, sulpiride,clozapine, trifluoperazine hydrochloride, fluphenazine hydrochloride,olanzapine, quetiapine fumarate, risperidone, aripiprazole etc.), CRFantagonist, other antianxiety drug (meprobamate etc.), tachykininantagonist (MK-869, saredutant etc.), medicament that acts onmetabotropic glutamate receptor, CCK antagonist, β3 adrenalineantagonist (amibegron hydrochloride etc.), GAT-1 inhibitor (tiagabinehydrochloride etc.), N-type calcium channel inhibitor, carbonicanhydrase II inhibitor, NMDA glycine moiety agonist, NMDA antagonist(memantine etc.), peripheral benzodiazepine receptor agonist,vasopressin antagonist, vasopressin V1b antagonist, vasopressin Viaantagonist, phosphodiesterase inhibitor, opioid antagonist, opioidagonist, uridine, nicotinic acid receptor agonist, thyroid hormone (T3,T4), TSH, TRH, MAO inhibitor (phenelzine sulfate, tranylcyprominesulfate, moclobemide etc.), 5-HT_(2A) antagonist, 5-HT_(2A) inverseagonist, COMT inhibitor (entacapone etc.), therapeutic drug for bipolardisorder (lithium carbonate, sodium valproate, lamotrigine, riluzole,felbamate etc.), cannabinoid CB1 antagonist (rimonabant etc.), FAAHinhibitor, sodium channel inhibitor, anti-ADHD drug (methylphenidatehydrochloride, methamphetamine hydrochloride etc.), therapeutic drug foralcoholism, therapeutic drug for autisma, therapeutic drug for chronicfatigue syndrome, therapeutic drug for spasm, therapeutic drug forfibromyalgia syndrome, therapeutic drug for headache, therapeutic drugfor insomnia (etizolam, zopiclone, triazolam, zolpidem, ramelteon,indiplon etc.), therapeutic drug for quitting smoking, therapeutic drugfor myasthenia gravis, therapeutic drug for cerebral infarction,therapeutic drug for mania, therapeutic drug for hypersomnia,therapeutic drug for pain, therapeutic drug for dysthymia, therapeuticdrug for autonomic ataxia, therapeutic drug for male and female sexualdysfunction, therapeutic drug for migraine, therapeutic drug forpathological gambler, therapeutic drug for restless legs syndrome,therapeutic drug for substance addiction, therapeutic drug foralcohol-related syndrome, therapeutic drug for irritable bowel syndrome,therapeutic drug for Alzheimer's disease (donepezil, galanthamine,memantine, rivastigmine etc.), therapeutic drug for Parkinson's disease(levodopa, carbidopa, benserazide, selegiline, rasagiline, zonisamide,entacapone, amantadine, talipexole, pramipexole, ropinirole, rotigotine,apomorphine, cabergoline, pergolide, bromocriptine, istradefylline,trihexyphenidyl, biperiden, piroheptine, profenamine, promethazine,droxidopa, combination of those drugs etc.), therapeutic drug forParkinson's disease dementia (rivastigmine), therapeutic drug fordementia with Lewy bodies (donepezil), therapeutic drug for ALS(riluzole, neurotrophic factor etc.), therapeutic drug for lipidabnormality such as cholesterol-lowering drug (statin series(pravastatin sodium, atorvastatin, simvastatin, rosuvastatin etc.),fibrate (clofibrate etc.), squalene synthetase inhibitor), therapeuticdrug for abnormal behavior or suppressant of dromomania due to dementia(sedatives, antianxiety drug etc.), apoptosis inhibitor, antiobesitydrug, therapeutic drug for diabetes, therapeutic drug for hypertension,therapeutic drug for hypotension, therapeutic drug for rheumatism(DMARD), anti-cancer agent, therapeutic drug for hypothyroidism (PTH),calcium receptor antagonist, sex hormone or a derivative thereof(progesterone, estradiol, estradiol benzoate etc.), neuronaldifferentiation promoter, nerve regeneration promoter, non-steroidalanti-inflammatory drug (meloxicam, tenoxicam, indomethacin, ibuprofen,celecoxib, rofecoxib, aspirin etc.), steroid (dexamethasone, cortisoneacetate etc.), anti-cytokine drug (TNF inhibitor, MAP kinase inhibitoretc.), antibody medicament, nucleic acid or nucleic acid derivative,aptamer drug and the like.

By combining the compound of the present invention and a concomitantdrug, a superior effect such as

(1) the dose can be reduced as compared to single administration of thecompound of the present invention or a concomitant drug,

(2) the drug to be combined with the compound of the present inventioncan be selected according to the condition of patients (mild case,severe case and the like),

(3) the period of treatment can be set longer by selecting a concomitantdrug having different action and mechanism from the compound of thepresent invention,

(4) a sustained treatment effect can be designed by selecting aconcomitant drug having different action and mechanism from the compoundof the present invention,

(5) a synergistic effect can be afforded by a combined use of thecompound of the present invention and a concomitant drug, and the like,can be achieved.

Hereinafter the compound of the present invention and a concomitant drugused in combination are referred to as the “combination agent of thepresent invention”.

When using the combination agent of the present invention, theadministration time of the compound of the present invention and theconcomitant drug is not restricted, and the compound of the presentinvention or a pharmaceutical composition thereof and the concomitantdrug or a pharmaceutical composition thereof can be administered to anadministration subject simultaneously, or may be administered atdifferent times. The dosage of the concomitant drug may be determinedaccording to the dose clinically used, and can be appropriately selecteddepending on an administration subject, administration route, disease,combination and the like.

The administration mode of the combination drug of the present inventionis not particularly restricted, and it is sufficient that the compoundof the present invention and the concomitant drug are combined inadministration. Examples of such administration mode include thefollowing methods: (1) administration of a single preparation obtainedby simultaneously processing the compound of the present invention andthe concomitant drug, (2) simultaneous administration of two kinds ofpreparations of the compound of the present invention and theconcomitant drug, which have been separately produced, by the sameadministration route, (3) administration of two kinds of preparations ofthe compound of the present invention and the concomitant drug, whichhave been separately produced, by the same administration route in astaggered manner, (4) simultaneous administration of two kinds ofpreparations of the compound of the present invention and theconcomitant drug, which have been separately produced, by differentadministration routes, (5) administration of two kinds of preparationsof the compound of the present invention and the concomitant drug, whichhave been separately produced, by different administration routes in astaggered manner (e.g., administration in the order of the compound ofthe present invention and the concomitant drug, or in the reverse order)and the like.

The combination drug of the present invention exhibits low toxicity. Forexample, the compound of the present invention or(and) theaforementioned concomitant drug can be combined with a pharmacologicallyacceptable carrier according to the known method to prepare apharmaceutical composition such as tablets (including sugar-coatedtablet and film-coated tablet), powders, granules, capsules (includingsoft capsule), liquids, injections, suppositories, sustained-releaseagents, etc. These compositions can be administered safely orally ornon-orally (e.g., topical, rectal, intravenous administration etc.).Injection can be administered intravenously, intramuscularly,subcutaneously, or by intraorgan administration or directly to thelesion.

Examples of the pharmacologically acceptable carriers usable for theproduction of a combination agent in the present invention, variousorganic or inorganic carrier substances conventionally used aspreparation materials can be mentioned. For solid preparations, forexample, excipient, lubricant, binder and disintegrant can be used. Forliquid preparations, for example, solvent, solubilizing agent,suspending agent, isotonic agent, buffering agent, soothing agent andthe like can be used. Where necessary, conventional preservative,antioxidant, colorant, sweetening agent, adsorbent, wetting agent andthe like can be used as appropriate.

Examples of the excipient include lactose, sucrose, D-mannitol, starch,corn starch, crystalline cellulose, light anhydrous silicic acid and thelike.

Examples of the lubricant include magnesium stearate, calcium stearate,talc, colloidal silica and the like.

Examples of the binder include crystalline cellulose, white sugar,D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose,gelatin, methylcellulose, carboxymethylcellulose sodium and the like.

Examples of the disintegrant include starch, carboxymethylcellulose,carboxymethylcellulose calcium, sodium carboxymethyl starch,L-hydroxypropylcellulose and the like.

Examples of the solvent include water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the solubilizing agent include polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like.

Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzetonium chloride, glycerinmonostearate and the like; hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like; and the like.

Examples of the isotonic agent include glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol and the like.

Examples of the buffer include buffer solutions such as phosphates,acetates, carbonates, citrates and the like.

Examples of the soothing agent include benzyl alcohol and the like.

Examples of the preservative include p-oxybenzoates, chlorobutanol,benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid andthe like.

Examples of the antioxidant include sulfite, ascorbic acid, α-tocopheroland the like.

The mixing ratio of the compound of the present invention to theconcomitant drug in the combination agent of the present invention canbe appropriately selected depending on an administration subject,administration route, diseases and the like.

For example, the content of the compound of the present invention in thecombination agent of the present invention differs depending on the formof a preparation, and usually from about 0.01 to about 100 wt %,preferably from about 0.1 to about 50 wt %, further preferably fromabout 0.5 to about 20 wt %, based on the preparation.

The content of the concomitant drug in the combination agent of thepresent invention differs depending on the form of a preparation, andusually from about 0.01 to about 100 wt %, preferably from about 0.1 toabout 50 wt %, further preferably from about 0.5 to about 20 wt %, basedon the preparation.

The content of additives such as a carrier and the like in thecombination agent of the present invention differs depending on the formof a preparation, and usually from about 1 to about 99.99 wt %,preferably from about 10 to about 90 wt %, based on the preparation.

When the compound of the present invention and a concomitant drug areseparately formulated into preparations, the contents thereof aresimilar to the above.

EXAMPLES

The present invention is explained in detail in the following byreferring to Examples, Experimental Examples and Formulation Examples,which are not to be construed as limitative, and the invention may bechanged within the scope of the present invention.

In the following Examples, the “room temperature” generally means about10° C. to about 35° C. The ratios indicated for mixed solvents arevolume mixing ratios, unless otherwise specified. % means wt %, unlessotherwise specified.

In silica gel column chromatography, NH means use ofaminopropylsilane-bound silica gel. In HPLC (high performance liquidchromatography), C18 means use of octadecyl-bound silica gel. The ratiosof elution solvents are volume mixing ratios, unless otherwisespecified.

The “osmium oxide (fixed catalyst I)” in Example means osmium oxide(VIII) (about 7% content) fixed to high solvent resistance polymer,which is commercially available from Wako Pure Chemical Industries,Ltd., unless otherwise specified. In addition, “sodium hydride” means a60% oil dispersion (mineral mixture).

In the following Examples, the following abbreviations are used.

THF: tetrahydrofuran

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

NBS: N-bromosuccinimide

AIBN: 2,2′-azobis(isobutyronitrile)

DME: 1,2-dimethoxyethane

[M+H]⁺: molecular ion peak

M: mol concentration

N: normal concentration

HPLC: high-performance liquid chromatography

tRn (n=1-4): retention time in high-performance liquid chromatography(the number means elution order)

¹H NMR (proton nuclear magnetic resonance spectrum) was measured byFourier-transform NMR. For the analysis, ACD/SpecManager (trade name)and the like were used. Peaks with very mild protons such as a hydroxygroup, an amino group and the like are not sometimes described.

MS (mass spectrum) was measured by LC/MS (liquid chromatography massspectrometer). As Ionization, ESI (Electro Spray Ionization) method, orAPCI (Atomospheric Pressure Chemical Ionization) method was used. Thedata indicates those actual measured value (found). Generally, molecularion peaks are observed. In the case of a compound having atert-butoxycarbonyl group (-Boc), a peak after elimination of atert-butoxycarbonyl group or tert-butyl group may be observed as afragment ion. In the case of a compound having a hydroxy group (—OH), apeak after elimination of H₂O may be observed as a fragment ion. In thecase of a salt, a molecular ion peak or fragment ion peak of free formis generally observed.

Example 1rac-2-(trans-2-hydroxycyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)isoindolin-1-oneA) methyl 5-bromo-2-(bromomethyl)benzoate

To a solution of methyl 5-bromo-2-methylbenzoate (5.27 g) intrifluoromethylbenzene (50.0 mL) were added AIBN (0.04 g) andN-bromosuccinimide (4.50 g), and the mixture was stirred at 90° C. for 4hr under argon atmosphere. The reaction mixture was diluted with ethylacetate, and the mixture was washed with saturated brine. The organiclayer was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (4.89 g).

¹H NMR (300 MHz, CDCl₃) δ 3.95 (3H, s), 4.90 (2H, s), 7.34 (1H, d, J=8.3Hz), 7.62 (1H, dd, J=8.2, 2.2 Hz), 8.11 (1H, d, J=2.1 Hz).

B) rac-6-bromo-2-(trans-2-hydroxycyclohexyl)isoindolin-1-one

To a solution of methyl 5-bromo-2-(bromomethyl)benzoate (0.50 g) in DMF(5.00 mL) were added trans-2-aminocyclohexanol hydrochloride (0.37 g)and N-ethyldiisopropylamine (1.42 mL), and the mixture was stirred at80° C. for 3 hr. To the reaction mixture was added 5% aqueous sodiumbicarbonate, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.22 g).

MS: [M+H]⁺ 312.0.

C)rac-6-((6-chloropyridin-3-yl)methyl)-2-(trans-2-hydroxycyclohexyl)isoindolin-1-one

To a solution ofrac-6-bromo-2-(trans-2-hydroxycyclohexyl)isoindolin-1-one (0.23 g) inTHF (3.0 mL) were added ((6-chloropyridin-3-yl)methyl)zinc(II) chloride(3.66 mL) and bis(tri-tert-butylphosphine)palladium(0) (0.07 g) underice-cooling, and the mixture was stirred at room temperature for 3 hrunder argon atmosphere. To the reaction mixture were added 5% aqueoussodium bicarbonate and ethyl acetate, the mixture was stirred, and theinsoluble substance was removed by filtration. The filtrate wasextracted with ethyl acetate, the organic layer was washed withsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.15 g).

MS: [M+H]⁺ 357.2.

D)rac-2-(trans-2-hydroxycyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)isoindolin-1-one

To a solution ofrac-6-((6-chloropyridin-3-yl)methyl)-2-(trans-2-hydroxycyclohexyl)isoindolin-1-one(0.09 g) in a mixed solvent of THF (9.00 mL)-water (3.00 mL) were added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.11 g), cesium carbonate (0.33 g) andbis(tri-tert-butylphosphine)palladium(0) (0.03 g), and the mixture wasstirred overnight at 85° C. under argon atmosphere. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (methanol/ethyl acetate) to give the title compound (0.03g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.27 (3H, brs), 1.53 (1H, brs), 1.66 (3H,brs), 1.94 (1H, brs), 3.54 (1H, brs), 3.78 (1H, d, J=7.0 Hz), 3.86 (3H,s), 4.05 (2H, s), 4.39 (2H, s), 4.71 (1H, d, J=5.5 Hz), 7.43-7.68 (5H,m), 7.92 (1H, s), 8.21 (1H, s), 8.45 (1H, s).

Example 2rac-5-chloro-2-(trans-2-hydroxycyclohexyl)-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-oneA) methyl4-chloro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

To a solution of methyl 5-bromo-4-chloro-2-hydroxybenzoate (2.40 g) intoluene (75.0 mL) were added bis(pinacolato)diboron (3.44 g), potassiumacetate (2.66 g) and trans-dichlorobis(triphenylphosphine)palladium(II)(0.32 g), and the mixture was stirred at 110° C. for 14 hr under argonatmosphere. The reaction mixture was allowed to be cooled to roomtemperature, water and ethyl acetate were added thereto, and the mixturewas partitioned. The organic layer was washed with water and saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (1.34 g).

MS: [M−H]⁺ 311.1.

B) methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-hydroxybenzoate

To a solution of methyl4-chloro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(0.15 g) in a mixed solvent of toluene (4.00 mL)-ethanol (0.80 mL)-water(0.80 mL) were added 1-(4-(bromomethyl)phenyl)-1H-pyrazole (0.11 g),tetrakis(triphenylphosphine)palladium(0) (0.06 g) and tripotassiumphosphate (0.26 g), and the mixture was stirred overnight at 100° C.under argon atmosphere. The reaction mixture was allowed to be cooled toroom temperature, water and ethyl acetate were added thereto, and themixture was partitioned. The organic layer was washed with water andsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.06 g).

¹H NMR (300 MHz, CDCl₃) δ 3.90-3.93 (3H, m), 4.06 (2H, s), 6.41-6.48(1H, m), 7.07 (1H, s), 7.23 (1H, s), 7.26 (1H, s), 7.57-7.66 (3H, m),7.71 (1H, d, J=1.5 Hz), 7.89 (1H, d, J=3.0 Hz), 10.69 (1H, s).

C) methyl5-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-hydroxybenzoate (0.18 g) in DMF(3.00 mL) were added sodium hydride (0.03 g) andN-phenylbis(trifluoromethanesulfonimide) (0.21 g) under ice-cooling, andthe mixture was stirred at room temperature for 4 hr. To the reactionmixture was added 1N hydrochloric acid, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium bicarbonate solution and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.18g).

MS: [M+H]⁺ 475.0.

D) methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-vinylbenzoate

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-(((trifluoromethyl)sulfonyl)oxy)benzoate(0.18 g) in DMF (3.50 mL) were added tributylvinyltin (0.17 mL),trans-dichlorobis(triphenylphosphine)palladium(II) (0.01 g) and lithiumchloride (0.12 g), and the mixture was stirred at 90° C. for 1 hr underargon atmosphere. To the reaction mixture was added aqueous potassiumfluoride solution, and the precipitated insoluble substance was removedby filtration through Celite. The filtrate was diluted with ethylacetate, and the mixture was washed with water and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.13 g).

MS: [M+H]⁺ 353.1.

E) methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-formylbenzoate

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-vinylbenzoate (0.12 g) in amixed solvent of acetone (2.00 mL)-acetonitrile (2.00 mL)-water (2.00mL) were added osmium oxide (fixed catalyst I) (0.04 g) and sodiumperiodate (0.36 g), and the mixture was stirred overnight at roomtemperature. The reaction mixture was filtered, and the filtrate wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure to give the title compoundas a crude product. This compound was used in the next step without anadditional purification.

F)rac-5-chloro-2-(trans-2-hydroxycyclohexyl)-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-one

A solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-formylbenzoate (0.12 g),trans-2-aminocyclohexanol hydrochloride (0.05 g), triethylamine (0.05mL) and anhydrous magnesium sulfate (0.08 g) in THF (2.50 mL) wasstirred at room temperature for 1 hr. The insoluble substance wasremoved by filtration, and the filtrate was concentrated under reducedpressure. The residue was diluted with methanol (2.50 mL) and THF (2.50mL), sodium triacetoxyborohydride (0.15 g) was added thereto, and themixture was stirred at room temperature for 3 hr. The reaction mixturewas diluted with ethyl acetate, and the mixture was washed with waterand saturated brine. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (0.05 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.23-1.36 (3H, m), 1.48-1.72 (4H, m),1.89-2.00 (1H, m), 3.49-3.62 (1H, m), 3.74-3.85 (1H, m), 4.20 (2H, s),4.42 (2H, s), 4.76 (1H, d, J=5.3 Hz), 6.48-6.54 (1H, m), 7.32 (2H, d,J=8.7 Hz), 7.66 (1H, s), 7.69-7.78 (4H, m), 8.43 (1H, d, J=2.6 Hz).

Example 3rac-2-(trans-2-hydroxycyclohexyl)-5-methoxy-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-oneA) methyl 5-bromo-2-hydroxy-4-methoxybenzoate

To a solution of 5-bromo-2-hydroxy-4-methoxybenzoic acid (2.00 g) inmethanol (10.0 mL) was added 0.6M (diazomethyl)trimethylsilane/hexanesolution (14.8 mL) under ice-cooling, and the mixture was stirred for 3hr. To the reaction mixture was added acetic acid (0.12 mL), and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (2.08 g).

¹H NMR (300 MHz, CDCl₃) δ 3.91 (3H, s), 3.93 (H, s), 6.49 (1H, s), 7.99(1H, s), 10.93 (1H, s).

B) methyl2-hydroxy-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

To a solution of methyl 5-bromo-2-hydroxy-4-methoxybenzoate (2.08 g) intoluene (70.0 mL) were added bis(pinacolato)diboron (3.03 g), potassiumacetate (2.35 g) and trans-dichlorobis(triphenylphosphine)palladium(II)(0.28 g), and the mixture was stirred at 110° C. for 14 hr under argonatmosphere. The reaction mixture was allowed to be cooled to roomtemperature, water and ethyl acetate were added thereto, and the mixturewas partitioned. The organic layer was washed with water and saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (1.93 g).

MS: [M−H]⁺ 309.2.

C) methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-hydroxy-4-methoxybenzoate

To a solution of methyl2-hydroxy-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(0.80 g) in a mixed solvent of DME (12.0 mL)-water (4.00 mL) were added1-(4-(bromomethyl)phenyl)-1H-pyrazole (0.62 g),tetrakis(triphenylphosphine)palladium(0) (0.15 g) and sodium carbonate(0.55 g), and the mixture was stirred overnight at 80° C. under argonatmosphere. The reaction mixture was allowed to be cooled to roomtemperature, water and ethyl acetate were added thereto, and the mixturewas partitioned. The organic layer was washed with water and saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.48 g).

MS: [M−H]⁺ 339.1.

D) methyl5-(4-(1H-pyrazol-1-yl)benzyl)-4-methoxy-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-2-hydroxy-4-methoxybenzoate (0.18 g) inDMF (4.00 mL) were added sodium hydride (0.03 g) andN-phenylbis(trifluoromethanesulfonimide) (0.21 g) under ice-cooling, andthe mixture was stirred at room temperature for 2 hr. To the reactionmixture was added 1N hydrochloric acid, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium bicarbonate solution and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.24g).

MS: [M+H]⁺ 471.1.

E) methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-methoxy-2-vinylbenzoate

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-4-methoxy-2-(((trifluoromethyl)sulfonyl)oxy)benzoate(0.23 g) in DMF (4.50 mL) were added tributylvinyltin (0.22 mL),trans-dichlorobis(triphenylphosphine)palladium(II) (0.02 g) and lithiumchloride (0.16 g), and the mixture was stirred at 90° C. for 1 hr underargon atmosphere. To the reaction mixture was added aqueous potassiumfluoride solution, and the precipitated insoluble substance was removedby filtration through Celite. The filtrate was diluted with ethylacetate, and the mixture was washed with water and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.16 g).

MS: [M+H]⁺ 349.1.

F) methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methoxybenzoate

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-4-methoxy-2-vinylbenzoate (0.16 g) in amixed solvent of acetone (2.20 mL)-acetonitrile (2.20 mL)-water (2.20mL) were added osmium oxide (fixed catalyst I) (0.06 g) and sodiumperiodate (0.48 g), and the mixture was stirred overnight at roomtemperature. The reaction mixture was filtered, and the filtrate wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure to give the title compound(0.16 g) as a crude product. This compound was used in the next stepwithout an additional purification.

MS: [M+H]⁺ 351.1.

G)rac-2-(trans-2-hydroxycyclohexyl)-5-methoxy-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-one

A solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methoxybenzoate (0.16 g),trans-2-aminocyclohexanol hydrochloride (0.07 g), triethylamine (0.06ml) and anhydrous magnesium sulfate (0.10 g) in THF (3.50 mL) wasstirred at room temperature for 2 hr. The insoluble substance wasremoved by filtration, and the filtrate was concentrated under reducedpressure. The residue was diluted with methanol (3.50 mL) and THF (3.50mL), sodium triacetoxyborohydride (0.19 g) was added thereto, and themixture was stirred at room temperature for 3.5 hr. The reaction mixturewas diluted with ethyl acetate, and the mixture was washed with waterand saturated brine. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (0.04 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.16-1.36 (3H, m), 1.42-1.74 (4H, m),1.88-2.00 (1H, m), 3.49-3.63 (1H, m), 3.70-3.83 (1H, m), 3.87 (3H, s),3.99 (2H, s), 4.37 (2H, s), 4.70 (1H, d, J=5.7 Hz), 6.48-6.53 (1H, m),7.20 (1H, s), 7.31 (2H, d, J=8.7 Hz), 7.41 (1H, s), 7.67-7.77 (3H, m),8.42 (1H, d, J=2.6 Hz).

Example 42-((1S,2S)-2-hydroxycyclopentyl)-5-methyl-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-oneA) 5-bromo-2-hydroxy-4-methylbenzoic acid

To a solution of 2-hydroxy-4-methylbenzoic acid (5.00 g) in acetic acid(70.0 mL) was added dropwise bromine (1.68 mL), and the mixture wasstirred at room temperature for 5.5 hr. To the reaction mixture wasadded water, and the precipitate was collected by filtration, and driedunder reduced pressure to give the title compound (6.78 g).

MS: [M−H]⁺ 229.0.

B) methyl 5-bromo-2-hydroxy-4-methylbenzoate

To a solution of 5-bromo-2-hydroxy-4-methylbenzoic acid (6.78 g) inmethanol (200 mL) was added dropwise sulfuric acid (6.77 mL), and themixture was stirred overnight at 70° C. The reaction mixture wasconcentrated under reduced pressure, the residue was neutralized withsaturated aqueous sodium bicarbonate solution under ice-cooling, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (6.56 g).

MS: [M−H]⁺ 243.0.

C) methyl2-hydroxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

To a solution of methyl 5-bromo-2-hydroxy-4-methylbenzoate (3.20 g) intoluene (95.0 mL) were added bis(pinacolato)diboron (4.97 g), potassiumacetate (3.84 g) and trans-dichlorobis(triphenylphosphine)palladium(II)(0.46 g), and the mixture was stirred at 110° C. for 15 hr under argonatmosphere. The reaction mixture was allowed to be cooled to roomtemperature, water and ethyl acetate were added thereto, and the mixturewas partitioned. The organic layer was washed with water and saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (3.84 g).

MS: [M+H]⁺ 293.1.

D) methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-hydroxy-4-methylbenzoate

To a solution of methyl2-hydroxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(1.40 g) in a mixed solvent of DME (21.0 mL)-water (7.00 mL) were added1-(4-(bromomethyl)phenyl)-H-pyrazole (1.14 g),tetrakis(triphenylphosphine)palladium(0) (0.28 g) and sodium carbonate(1.02 g), and the mixture was stirred overnight at 80° C. under argonatmosphere. The reaction mixture was allowed to be cooled to roomtemperature, water and ethyl acetate were added thereto, and the mixturewas partitioned. The organic layer was washed with water and saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.85 g).

MS: [M+H]⁺ 323.1.

E) methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-2-hydroxy-4-methylbenzoate (0.85 g) in DMF(17.0 mL) were added sodium hydride (0.13 g) andN-phenylbis(trifluoromethanesulfonimide) (1.03 g) under ice-cooling, andthe mixture was stirred at room temperature for 3 hr. To the reactionmixture was added 1N hydrochloric acid, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium bicarbonate solution and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (1.13g).

MS: [M+H]⁺ 455.1.

F) methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-methyl-2-vinylbenzoate

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-4-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (1.12 g) in DMF (25.0 mL) were addedtributylvinyltin (1.08 mL),trans-dichlorobis(triphenylphosphine)palladium(II) (0.09 g) and lithiumchloride (0.77 g), and the mixture was stirred at 90° C. 1.5 hr underargon atmosphere. To the reaction mixture was added aqueous potassiumfluoride solution, and the precipitated insoluble substance was removedby filtration through Celite. The filtrate was diluted with ethylacetate, and the mixture was washed with water and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.73 g).

MS: [M+H]⁺ 333.1.

G) methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methylbenzoate

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-4-methyl-2-vinylbenzoate (0.31 g) in amixed solvent of acetone (6.20 mL)-acetonitrile (6.20 mL)-water (6.20mL) were added osmium oxide (fixed catalyst I) (0.12 g) and sodiumperiodate (1.00 g), and the mixture was stirred overnight at roomtemperature. The reaction mixture was filtered, and the filtrate wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure to give the title compound(0.16 g) as a crude product. This compound was used in the next stepwithout an additional purification.

MS: [M+H]⁺ 335.1.

H)2-((1S,2S)-2-hydroxycyclopentyl)-5-methyl-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-one

A solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methylbenzoate (0.16 g),(1S,2S)-2-aminocyclopentanol hydrochloride (0.06 g), triethylamine (0.07mL) and anhydrous magnesium sulfate (0.11 g) in THF (3.10 mL) wasstirred at room temperature for 3 hr. The insoluble substance wasremoved by filtration, and the filtrate was concentrated under reducedpressure. The residue was diluted with methanol (3.10 mL) and THF (3.10mL), sodium triacetoxyborohydride (0.20 g) was added thereto, and themixture was stirred overnight at room temperature. The reaction mixturewas diluted with ethyl acetate, and the mixture was washed with waterand saturated brine. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (71 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.45-1.97 (6H, m), 2.32 (3H, s), 4.00-4.28(4H, m), 4.40 (2H, s), 4.90 (1H, d, J=4.9 Hz), 6.49-6.56 (1H, m), 7.25(2H, d, J=8.5 Hz), 7.41 (2H, d, J=12.8 Hz), 7.67-7.81 (3H, m), 8.44 (1H,d, J=2.5 Hz).

Example 5rac-6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-(trans-2-hydroxycyclohexyl)-5-methylisoindolin-1-oneA) methyl 5-((6-chloropyridin-3-yl)methyl)-2-hydroxy-4-methylbenzoate

To a solution of methyl 5-bromo-2-hydroxy-4-methylbenzoate (0.61 g) inTHF (20.0 mL) were added 0.5M (2-chloro-5-pyridyl)methylzincchloride/THF solution (12.5 mL) andbis(tri-tert-butylphosphine)palladium(0) (0.13 g), and the mixture wasstirred overnight at room temperature under argon atmosphere. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.52 g).

MS: [M+H]⁺ 292.0.

B) methyl5-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-hydroxy-4-methylbenzoate

To a solution of methyl5-((6-chloropyridin-3-yl)methyl)-2-hydroxy-4-methylbenzoate (0.09 g) ina mixed solvent of THF (2.40 mL)-water (0.80 mL) were added1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.14 g), potassium carbonate (0.17 g) andtetrakis(triphenylphosphine)palladium(0) (0.03 g), and the mixture wasstirred overnight at 85° C. under argon atmosphere. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.09 g).

MS: [M+H]⁺ 352.1.

C) methyl5-((6-(1,3-dimethyl-H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl5-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-hydroxy-4-methylbenzoate(0.27 g) in DMF (6.00 mL) were added sodium hydride (0.04 g) andN-phenylbis(trifluoromethanesulfonimide) (0.30 g) under ice-cooling, andthe mixture was stirred at room temperature for 2 hr. To the reactionmixture was added 1N hydrochloric acid, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium bicarbonate solution and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.26g).

MS: [M+H]⁺ 484.1.

D) methyl5-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-methyl-2-vinylbenzoate

To a solution of methyl5-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate(0.26 g) in DMF (5.5 mL) were added tributylvinyltin (0.24 mL),trans-dichlorobis(triphenylphosphine)palladium(II) (0.02 g) and lithiumchloride (0.17 g), and the mixture was stirred at 90° C. for 1.5 hrunder argon atmosphere. To the reaction mixture was added aqueouspotassium fluoride solution, and the precipitated insoluble substancewas removed by filtration through Celite. The filtrate was diluted withethyl acetate, and the mixture was washed with water and saturatedbrine. The organic layer was dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.18 g).

MS: [M+H]⁺ 362.1.

E) methyl5-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-formyl-4-methylbenzoate

To a solution of methyl5-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-methyl-2-vinylbenzoate(0.18 g) in a mixed solvent of acetone (2.80 mL)-acetonitrile (2.80mL)-water (2.80 mL) were added osmium oxide (fixed catalyst I) (0.06 g)and sodium periodate (0.53 g), and the mixture was stirred overnight atroom temperature. The reaction mixture was filtered, and the filtratewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure to give the titlecompound (0.18 g) as a crude product. This compound was used in the nextstep without an additional purification.

MS: [M+H]⁺ 364.2.

F)rac-6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-(trans-2-hydroxycyclohexyl)-5-methylisoindolin-1-one

A solution of methyl5-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-formyl-4-methylbenzoate(0.09 g), trans-2-aminocyclohexanol hydrochloride (0.04 g),triethylamine (0.04 mL) and anhydrous magnesium sulfate (0.06 g) in THF(2.00 mL) was stirred at room temperature for 1.5 hr. The insolublesubstance was removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was diluted with methanol (2.00 mL)and THF (2.00 mL), sodium triacetoxyborohydride (0.11 g) was addedthereto, and the mixture was stirred overnight at room temperature. Thereaction mixture was diluted with ethyl acetate, and the mixture waswashed with water and saturated brine. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.05g).

¹H NMR (300 MHz, CDCl₃) δ 1.27-1.59 (5H, m), 1.81 (2H, d, J=11.7 Hz),1.92 (1H, d, J=13.2 Hz), 2.13-2.24 (1H, m), 2.35 (3H, s), 2.49 (3H, s),3.61-3.73 (1H, m), 3.87 (3H, s), 4.03 (2H, s), 4.06-4.15 (1H, m),4.29-4.47 (2H, m), 7.27-7.39 (3H, m), 7.64 (1H, s), 7.76 (1H, s), 8.42(1H, d, J=1.5 Hz).

Example 6rac-2-(trans-2-hydroxycyclohexyl)-5-methyl-6-((2′-methyl-2,4′-bipyridin-5-yl)methyl)isoindolin-1-oneA) methyl2-hydroxy-4-methyl-5-((2′-methyl-[2,4′-bipyridine]-5-yl)methyl)benzoate

To a solution of methyl5-((6-chloropyridin-3-yl)methyl)-2-hydroxy-4-methylbenzoate (0.35 g) ina mixed solvent of THF (8.40 mL)-water (2.80 mL) were added2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.53g), potassium carbonate (0.66 g) andtetrakis(triphenylphosphine)palladium(0) (0.14 g), and the mixture wasstirred overnight at 85° C. under argon atmosphere. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.35 g).

MS: [M+H]⁺ 349.1.

B) methyl4-methyl-5-((2′-methyl-[2,4′-bipyridine]-5-yl)methyl)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl2-hydroxy-4-methyl-5-((2′-methyl-[2,4′-bipyridine]-5-yl)methyl)benzoate(0.34 g) in DMF (7.00 mL) were added sodium hydride (0.05 g) andN-phenylbis(trifluoromethanesulfonimide) (0.39 g) under ice-cooling, andthe mixture was stirred at room temperature for 2.5 hr. To the reactionmixture was added 1N hydrochloric acid, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium bicarbonate solution and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.22g).

MS: [M+H]⁺ 481.1.

C) methyl4-methyl-5-((2′-methyl-[2,4′-bipyridine]-5-yl)methyl)-2-vinylbenzoate

To a solution of methyl4-methyl-5-((2′-methyl-[2,4′-bipyridine]-5-yl)methyl)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate(0.21 g) in DMF (4.00 mL) were added tributylvinyltin (0.19 mL),trans-dichlorobis(triphenylphosphine)palladium(II) (0.02 g) and lithiumchloride (0.14 g), and the mixture was stirred at 90° C. for 1.5 hrunder argon atmosphere. To the reaction mixture was added aqueouspotassium fluoride solution, and the precipitated insoluble substancewas removed by filtration through Celite. The filtrate was diluted withethyl acetate, and the mixture was washed with water and saturatedbrine. The organic layer was dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.11 g).

MS: [M+H]⁺ 359.1.

D) methyl2-formyl-4-methyl-5-((2′-methyl-[2,4′-bipyridine]-5-yl)methyl)benzoate

To a solution of methyl4-methyl-5-((2′-methyl-[2,4′-bipyridine]-5-yl)methyl)-2-vinylbenzoate(0.11 g) in a mixed solvent of acetone (2.00 mL)-acetonitrile (2.00mL)-water (2.00 mL) were added osmium oxide (fixed catalyst I) (0.04 g)and sodium periodate (0.33 g), and the mixture was stirred overnight atroom temperature. The reaction mixture was filtered, and the filtratewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure to give the titlecompound (0.11 g) as a crude product. This compound was used in the nextstep without an additional purification.

MS: [M+H]⁺ 361.2.

E)rac-2-(trans-2-hydroxycyclohexyl)-5-methyl-6-((2′-methyl-2,4′-bipyridin-5-yl)methyl)isoindolin-1-one

A solution of methyl2-formyl-4-methyl-5-((2′-methyl-[2,4′-bipyridine]-5-yl)methyl)benzoate(0.06 g), trans-2-aminocyclohexanol hydrochloride (0.02 g),triethylamine (0.02 mL) and anhydrous magnesium sulfate (0.04 g) in THF(1.20 mL) was stirred at room temperature for 1.5 hr. The insolublesubstance was removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was diluted with methanol (1.20 mL)and THF (1.20 mL), sodium triacetoxyborohydride (0.06 g) was addedthereto, and the mixture was stirred overnight at room temperature. Thereaction mixture was diluted with ethyl acetate, and the mixture waswashed with water and saturated brine. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.02g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.23-1.36 (3H, m), 1.45-1.72 (4H, m),1.90-2.01 (1H, m), 2.35 (3H, s), 2.54 (3H, s), 3.58 (1H, dt, J=11.8, 5.6Hz), 3.74-3.85 (1H, m), 4.16 (2H, s), 4.38 (2H, s), 4.73 (1H, d, J=5.7Hz), 7.41 (1H, s), 7.47 (1H, s), 7.66 (1H, dd, J=7.9, 2.3 Hz), 7.81 (1H,d, J=5.3 Hz), 7.90 (1H, s), 8.01 (1H, d, J=8.3 Hz), 8.53 (1H, d, J=5.3Hz), 8.61 (1H, d, J=1.5 Hz).

Example 73-fluoro-2-(5-methyl-1-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)-1,3-dihydro-2H-isoindol-2-yl)benzonitrileA)6-(4-(1H-pyrazol-1-yl)benzyl)-2-(2,4-dimethoxybenzyl)-5-methylisoindolin-1-one

A solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methylbenzoate (0.30 g),(2,4-dimethoxyphenyl)methanamine (0.02 g) and anhydrous magnesiumsulfate (0.21 g) in THF (6.00 mL) was stirred at room temperature for1.5 hr. The insoluble substance was removed by filtration, and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with methanol (6.00 mL) and THF (6.00 mL), sodiumtriacetoxyborohydride (0.38 g) was added thereto, and the mixture wasstirred overnight at room temperature. The reaction mixture was dilutedwith ethyl acetate, and the mixture was washed with water and saturatedbrine. The organic layer was dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.25 g).

MS: [M+H]⁺ 454.2.

B) 6-(4-(1H-pyrazol-1-yl)benzyl)-5-methylisoindolin-1-one

To a solution of6-(4-(1H-pyrazol-1-yl)benzyl)-2-(2,4-dimethoxybenzyl)-5-methylisoindolin-1-one(0.24 g) in trifluoroacetic acid (4.34 mL) was added anisole (0.23 mL),and the mixture was stirred at 80° C. for 2 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.15 g).

MS: [M+H]⁺ 304.1.

C)3-fluoro-2-(5-methyl-1-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)-1,3-dihydro-2H-isoindol-2-yl)benzonitrile

To a solution of 6-(4-(1H-pyrazol-1-yl)benzyl)-5-methylisoindolin-1-one(0.05 g) in DMF (1.00 mL) were added potassium carbonate (0.07 g) and2,3-difluorobenzonitrile (0.05 g), and the mixture was stirred overnightat 150° C. under argon atmosphere. The reaction mixture was diluted withwater and ethyl acetate, and the mixture was partitioned. The organiclayer was washed with water and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) and then HPLC (water/methanol) togive the title compound (7.80 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.39 (3H, s), 4.16 (2H, s), 4.90 (2H, s),6.50-6.55 (1H, m), 7.31 (2H, d, J=8.5 Hz), 7.54 (1H, s), 7.62 (1H, s),7.65-7.73 (2H, m), 7.75-7.91 (4H, m), 8.45 (1H, d, J=2.4 Hz).

Example 85-methyl-6-(4-(1H-pyrazol-1-yl)benzyl)-2-(tetrahydro-2H-pyran-4-yl)isoindolin-1-one

A solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methylbenzoate (0.10 g),tetrahydro-2H-pyran-4-amine (0.03 g) and anhydrous magnesium sulfate(0.07 g) in THF (2.00 mL) was stirred at room temperature for 1 hr. Theinsoluble substance was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The residue was diluted withmethanol (2.00 mL) and THF (2.00 mL), sodium triacetoxyborohydride (0.13g) was added thereto, and the mixture was stirred overnight at roomtemperature. The reaction mixture was diluted with ethyl acetate, andthe mixture was washed with water and saturated brine. The organic layerwas dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.04 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.59-1.70 (2H, m), 1.80 (2H, qd, J=12.1, 4.3Hz), 2.32 (3H, s), 3.3-3.49 (2H, m), 3.94 (2H, dd, J=11.1, 4.0 Hz), 4.09(2H, s), 4.18-4.29 (1H, m), 4.41 (2H, s), 6.49-6.55 (1H, m), 7.25 (2H,d, J=8.3 Hz), 7.42 (2H, d, J 13.9 Hz), 7.70-7.78 (3H, m), 8.44 (1H, d,J=2.6 Hz).

Example 9rac-5-cyclopropyl-2-(trans-2-hydroxycyclopentyl)-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-oneA) methyl 4-bromo-2-hydroxybenzoate

To a solution of 4-bromo-2-hydroxybenzoic acid (15.0 g) in methanol (150mL) was added dropwise thionyl chloride (10.1 mL) under ice-cooling, andthe mixture was stirred overnight at 70° C. under argon atmosphere. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (14.2 g).

¹H NMR (300 MHz, DMSO-d₆) δ 3.88 (3H, s), 7.10-7.18 (1H, m), 7.21-7.28(1H, m), 7.69 (1H, d, J=8.3 Hz), 10.65 (1H, s).

B) methyl 4-cyclopropyl-2-hydroxybenzoate

To a solution of methyl 4-bromo-2-hydroxybenzoate (3.00 g) in toluene(30.0 mL) were added tris(dibenzylideneacetone)dipalladium(0) (0.60 g),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.53 g),cyclopropylboronic acid (2.79 g) and sodium carbonate (3.44 g), and themixture was stirred overnight at 100° C. under argon atmosphere. Thereaction mixture was diluted with ethyl acetate, and the mixture waswashed with water and saturated brine. The organic layer was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (1.80 g).

¹H NMR (300 MHz, DMSO-d₆) δ 0.70-0.80 (2H, m), 0.97-1.07 (2H, m),1.85-1.99 (1H, m), 3.87 (3H, s), 6.61-6.73 (2H, m), 7.65 (1H, d, J=7.9Hz), 10.50 (1H, s).

C) methyl 5-bromo-4-cyclopropyl-2-hydroxybenzoate

To a solution of methyl 4-cyclopropyl-2-hydroxybenzoate (1.80 g) inacetic acid (15.0 mL) was added dropwise bromine (1.57 g) underice-cooling. The mixture was stirred at room temperature for 2 hr, tothe reaction mixture was added water, and the resulting solid wascollected by filtration. The obtained solid was dried under reducedpressure to give the title compound (2.28 g).

¹H NMR (300 MHz, DMSO-d₆) δ 0.69-0.82 (2H, m), 1.02-1.12 (2H, m),2.04-2.18 (1H, m), 3.87 (3H, s), 6.58 (1H, s), 7.88 (1H, s), 10.38 (1H,s).

D) methyl4-cyclopropyl-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

To a solution of methyl 5-bromo-4-cyclopropyl-2-hydroxybenzoate (1.05 g)in toluene (30 mL) were added bis(pinacolato)diboron (1.48 g), potassiumacetate (1.14 g) and trans-dichlorobis(triphenylphosphine)palladium(II)(0.14 g), and the mixture was stirred at 110° C. for 15 hr under argonatmosphere. The reaction mixture was allowed to be cooled to roomtemperature, water and ethyl acetate were added thereto, and the mixturewas partitioned. The organic layer was washed with water and saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.72 g).

MS: [M+H]⁺ 319.2.

E) methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-cyclopropyl-2-hydroxybenzoate

To a solution of methyl4-cyclopropyl-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(0.36 g) in a mixed solvent of DME (5.70 mL)-water (1.90 mL) were added1-(4-(bromomethyl)phenyl)-1H-pyrazole (0.27 g),tetrakis(triphenylphosphine)palladium(0) (0.07 g) and sodium carbonate(0.24 g), and the mixture was stirred overnight at 80° C. under argonatmosphere. The reaction mixture was allowed to be cooled to roomtemperature, water and ethyl acetate were added thereto, and the mixturewas partitioned. The organic layer was washed with water and saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.26 g).

MS: [M+H]⁺ 349.1.

F) methyl5-(4-(1H-pyrazol-1-yl)benzyl)-4-cyclopropyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-4-cyclopropyl-2-hydroxybenzoate (0.25 g)in DMF (5.00 mL) were added sodium hydride (0.04 g) andN-phenylbis(trifluoromethanesulfonimide) (0.29 g) under ice-so cooling,and the mixture was stirred at room temperature for 3 hr. To thereaction mixture was added 1N hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium bicarbonate solution and saturated brine, anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.33g).

MS: [M+H]⁺ 481.1.

G) methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-cyclopropyl-2-vinylbenzoate

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-4-cyclopropyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate(0.33 g) in DMF (6.60 mL) were added tributylvinyltin (0.30 mL),trans-dichlorobis(triphenylphosphine)palladium(II) (0.02 g) and lithiumchloride (0.22 g), and the mixture was stirred at 90° C. for 1.5 hrunder argon atmosphere. To the reaction mixture was added aqueouspotassium fluoride solution, and the precipitated insoluble substancewas removed by filtration through Celite. The filtrate was diluted withethyl acetate, and the mixture was washed with water and saturatedbrine. The organic layer was dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.22 g).

MS: [M+H]⁺ 359.2.

H) methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-cyclopropyl-2-formylbenzoate

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-4-cyclopropyl-2-vinylbenzoate (0.22 g) ina mixed solvent of acetone (4.40 ml)-acetonitrile (4.40 mL)-water (4.40mL) were added osmium oxide (fixed catalyst I) (0.08 g) and sodiumperiodate (0.65 g), and the mixture was stirred overnight at roomtemperature. The reaction mixture was filtered, and the filtrate wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure to give the title compound(0.22 g) as a crude product. This compound was used in the next stepwithout an additional purification.

MS: [M+H]⁺ 361.2.

I)rac-5-cyclopropyl-2-(trans-2-hydroxycyclopentyl)-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-one

A solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-4-cyclopropyl-2-formylbenzoate (0.11 g),trans-2-aminocyclopentanol hydrochloride (0.04 g), triethylamine (0.04mL) and anhydrous magnesium sulfate (0.07 g) in THF (2.20 mL) wasstirred at room temperature for 5 hr. The insoluble substance wasremoved by filtration, and the filtrate was concentrated under reducedpressure. The residue was diluted with methanol (2.20 mL) and THF (2.20mL), sodium triacetoxyborohydride (0.13 g) was added thereto, and themixture was stirred overnight at room temperature. The reaction mixturewas diluted with ethyl acetate, and the mixture was washed with waterand saturated brine. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (0.06 g).

¹H NMR (300 MHz, DMSO-d₆) δ 0.62-0.70 (2H, m), 0.89-0.98 (2H, m),1.47-1.75 (4H, m), 1.79-2.07 (3H, m), 4.06-4.25 (2H, m), 4.27 (2H, s),4.38 (2H, s), 4.90 (1H, d, J=4.9 Hz), 6.49-6.54 (1H, m), 7.19 (1H, s),7.28 (2H, d, J=8.3 Hz), 7.44 (1H, s), 7.70-7.78 (3H, m), 8.44 (1H, d,J=2.3 Hz).

Example 10rac-4-chloro-2-(trans-2-hydroxycyclohexyl)-6-(4-(1H-pyrazol-1-yl)benzyl)-5-(trifluoromethyl)isoindolin-1-oneA) 2-chloro-1-(methoxymethoxy)-3-(trifluoromethyl)benzene

To a suspension of sodium hydride (3.78 g) in THF (150 mL) were addeddropwise 2-chloro-3-hydroxybenzotrifluoride (12.4 g) and chloromethylmethyl ether (6.10 g) under ice-cooling, and the mixture was stirred at12° C. for 16 hr. The reaction mixture was poured into saturated aqueoussodium chloride solution, and the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure to give the titlecompound (16.8 g) as a crude product.

¹H NMR (400 MHz, CDCl₃) δ 3.53 (3H, s), 5.28 (2H, s), 7.27-7.32 (1H, m),7.34-7.39 (2H, m).

B) methyl 3-chloro-2-[(methoxycarbonyl)oxy]-4-(trifluoromethyl)benzoate

To a solution of 2-chloro-1-(methoxymethoxy)-3-(trifluoromethyl)benzene(11.8 g) in THF (100 mL) was added dropwise n-butyllithium (2.5M hexanesolution) (21.0 mL) at −10° C., and the mixture was stirred for 2 hr.Then, to the reaction mixture was added dropwise a solution of methylchloroformate (23.0 g) in THF (50.0 mL), and the mixture was stirred at10° C. for 16 hr. The reaction mixture was poured into saturated aqueoussodium bicarbonate solution, and the mixture was extracted with ethylacetate (×2). The organic layer was dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by flash silica gel column chromatography (ethylacetate/petroleum ether) to give the title compound (6.00 g).

¹H NMR (400 MHz, CDCl₃) δ 3.93 (3H, s), 3.99 (3H, s), 7.69 (1H, d, J=8.4Hz), 8.00 (1H, d, J=8.4 Hz).

C) methyl 3-chloro-2-hydroxy-4-(trifluoromethyl)benzoate

To a solution of methyl3-chloro-2-[(methoxycarbonyl)oxy]-4-(trifluoromethyl)benzoate (6.00 g)in methanol (60.0 mL) was added potassium carbonate (8.00 g), and themixture was stirred at 15° C. for 16 hr. The reaction mixture wasfiltered, the filtrate was neutralized with 1N hydrochloric acid, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure to give the titlecompound (3.50 g).

¹H NMR (400 MHz, CDCl₃) δ 4.06 (3H, s), 7.29 (1H, d, J=5.2 Hz), 7.90(1H, d, J=8.0 Hz), 11.55 (1H, brs).

D) methyl 5-bromo-3-chloro-2-hydroxy-4-(trifluoromethyl)benzoate

To a solution of methyl 3-chloro-2-hydroxy-4-(trifluoromethyl)benzoate(6.30 g) in DMF (65.0 mL) was added N-bromosuccinimide (4.41 g), and themixture was stirred at 15° C. for 16 hr. The reaction mixture was pouredinto water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure togive the title compound (7.00 g).

¹H NMR (400 MHz, CDCl₃) δ 4.03 (3H, s), 8.13 (1H, s), 11.43 (1H, brs).

E) methyl3-chloro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzoate

To a solution of methyl5-bromo-3-chloro-2-hydroxy-4-(trifluoromethyl)benzoate (4.80 g) intoluene (70.0 mL) were added bis(pinacolato)diboron (5.48 g), potassiumacetate (4.20 g) and trans-dichlorobis(triphenylphosphine)palladium(II)(0.51 g), and the mixture was stirred at 110° C. for 16 hr under argonatmosphere. The reaction mixture was allowed to be cooled to roomtemperature, and filtered, and the filtrate was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by flash silica gel column chromatography (ethylacetate/petroleum ether) to give the title compound (2.10 g).

¹H NMR (400 MHz, CDCl₃) δ 1.37 (12H, s), 4.02 (3H, s), 7.88 (1H, s),11.57 (1H, brs).

F) ethyl 4-(1H-pyrazol-1-yl)benzoate

To a solution of ethyl 4-fluorobenzoate (105 g) in DMSO (250 mL) wereadded pyrazole (34.0 g) and potassium carbonate (138 g), and the mixturewas heated with stirring at 130° C. for 16 hr. The reaction mixture wasdiluted with water, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure to give the title compound (73.7 g).

¹H NMR (400 MHz, CDCl₃) δ 1.40 (3H, t, J=7.2 Hz), 4.38 (2H, q, J=7.2Hz), 6.49 (1H, t, J=2.0 Hz), 7.75 (1H, d, J=1.6 Hz), 7.77 (2H, d, J=8.8Hz), 7.99 (1H, d, J=2.4 Hz), 8.12 (2H, d, J=8.8 Hz).

G) [4-(1H-pyrazol-1-yl)phenyl]methanol

To a solution of ethyl 4-(1H-pyrazol-1-yl)benzoate (73.7 g) in THF (500mL) were added sodium borohydride (19.5 g) and calcium chloride (56.8 g)under ice-cooling, and the mixture was stirred at room temperature for16 hr, and then heated with reflux for 2 days. The reaction mixture wasdiluted with 1N hydrochloric acid, and the mixture was extracted withethyl acetate (×4). The organic layer was washed with saturated brine,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was washed with tert-butylmethyl ether to give the title compound (49.6 g).

¹HNMR (400 MHz, CDCl₃) δ 2.79 (1H, brs), 4.68 (2H, s), 6.45 (1H, t,J=2.0 Hz), 7.38 (2H, d, J=7.6 Hz), 7.61 (2H, d, J=8.4 Hz), 7.70 (1H, s),7.89 (1H, d, J=1.6 Hz).

H) 1-[4-(chloromethyl)phenyl]-1H-pyrazole

To a solution of [4-(1H-pyrazol-1-yl)phenyl]methanol (24.0 g) in1,2-dichloroethane (200 mL) was added dropwise thionyl chloride (26.3 g)under ice-cooling, and the mixture was stirred at room temperature for16 hr. The reaction mixture was concentrated under reduced pressure, andthe residue was washed with tert-butyl methyl ether to give the titlecompound (23.5 g).

¹HNMR (400 MHz, CDCl₃) δ 4.62 (2H, s), 6.48 (1H, t, J=2.0 Hz), 7.47 (2H,d, J=8.8 Hz), 7.69 (2H, d, J=8.8 Hz), 7.73 (1H, d, J=2.0 Hz), 7.93 (1H,d, J=2.4 Hz).

I) methyl3-chloro-2-hydroxy-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoateand3-chloro-2-hydroxy-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoicacid

To a solution of methyl3-chloro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzoate(1.50 g) in 1,4-dioxane (30.0 mL) were added1-(4-(chloromethyl)phenyl)-1H-pyrazole (0.76 g),tetrakis(triphenylphosphine)palladium(0) (0.23 g) and tripotassiumphosphate trihydrate (2.10 g), and the mixture was stirred at 90° C. for16 hr under nitrogen atmosphere. The reaction mixture was allowed to becooled to room temperature, water and ethyl acetate were added thereto,and the mixture was partitioned. The organic layer was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by flash silica gel columnchromatography (ethyl acetate/petroleum ether) to give methyl3-chloro-2-hydroxy-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoate(0.12 g) and3-chloro-2-hydroxy-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoicacid (0.70 g).

¹H NMR (400 MHz, CDCl₃) δ 3.98 (3H, s), 4.21 (2H, d, J=2.0 Hz), 6.40(1H, t, J=2.0 Hz), 7.12 (2H, d, J=8.4 Hz), 7.62 (2H, d, J=8.4 Hz), 7.68(1H, s), 7.72 (1H, d, J=1.6 Hz), 7.90 (1H, d, J=2.4 Hz), 11.40 (1H,brs).

¹H NMR (400 MHz, CDCl₃) δ 3.49 (2H, s), 4.18 (1H, s), 6.40-6.52 (1H, m),7.05-7.24 (2H, m), 7.44-7.58 (2H, m), 7.78-7.95 (3H, m). An activeproton was not observed.

J) methyl3-chloro-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate

To a solution of methyl3-chloro-2-hydroxy-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoate(0.15 g) in dichloromethane (5.00 mL) were added triethylamine (0.05 g)and trifluoromethanesulfonic anhydride (0.14 g) under ice-cooling, andthe mixture was stirred at room temperature for 16 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure to give the titlecompound (0.24 g) as a crude product. This compound was used in the nextstep without an additional purification.

MS: [M+H]⁺ 542.9.

K) methyl3-chloro-2-ethenyl-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoate

To a solution of methyl3-chloro-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate(0.24 g) in THF (5.00 mL)-water (5.00 mL) were added potassiumvinyltrifluoroborate (0.07 g), cesium carbonate (0.24 g) andtetrakis(triphenylphosphine)palladium(0) (0.01 g), and the mixture wasstirred at 90° C. for 16 hr under nitrogen atmosphere. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by prep-thin layer chromatography (ethyl acetate/petroleumether) to give the title compound (0.08 g).

¹H NMR (400 MHz, CDCl₃) δ 3.83 (3H, s), 4.28 (2H, d, J=2.0 Hz), 5.32(1H, d, J=18.0 Hz), 5.54 (1H, d, J=12.4 Hz), 6.43-6.48 (1H, t, J=2.4Hz), 6.94 (1H, dd, J=17.6, 11.2 Hz), 7.15 (2H, d, J=8.4 Hz), 7.37 (1H,s), 7.63 (2H, d, J=8.8 Hz), 7.71 (1H, d, J=1.2 Hz), 7.90 (1H, d, J=2.4Hz).

L) ethyl3-chloro-2-hydroxy-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoate

To a solution of3-chloro-2-hydroxy-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoicacid (0.60 g) in dichloromethane (20.0 mL) was added oxalyl chloride(0.29 g) under ice-cooling, and the mixture was stirred at 15° C. for 16hr. The reaction mixture was added to a solution of triethylamine (2.00mL) in ethanol (40.0 mL), and the mixture was stirred for 1 hr. Themixture was concentrated under reduced pressure, and the residue wasdiluted with ethyl acetate. The mixture was washed with 1N hydrochloricacid and saturated aqueous sodium bicarbonate solution, and the organiclayer was concentrated under reduced pressure. The residue was purifiedby flash silica gel column chromatography (ethyl acetate/petroleumether) to give the title compound (0.20 g).

¹H NMR (400 MHz, CDCl₃) δ 1.41 (3H, t, J=7.2 Hz), 4.22 (2H, d, J=2.0Hz), 4.45 (2H, q, J=7.2 Hz), 6.42-6.49 (1H, m), 7.11 (2H, d, J=8.8 Hz),7.59-7.64 (2H, m), 7.66-7.73 (2H, m), 7.89 (1H, d, J=2.4 Hz), 11.49 (1H,brs).

M) ethyl3-chloro-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate

To a solution of ethyl3-chloro-2-hydroxy-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoate(0.20 g) in dichloromethane (15.0 mL) were added triethylamine (0.10 g)and trifluoromethanesulfonic anhydride (0.27 g) under ice-cooling, andthe mixture was stirred at room temperature for 16 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure to give the titlecompound (0.25 g) as a crude product. This compound was used in the nextstep without an additional purification.

MS: [M+H]⁺ 557.0.

N) ethyl3-chloro-2-ethenyl-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoate

To a solution of ethyl3-chloro-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate(0.25 g) in THF (8.00 mL)-water (5.00 mL) were added potassiumvinyltrifluoroborate (0.13 g), cesium carbonate (0.46 g) andtetrakis(triphenylphosphine)palladium(0) (0.03 g), and the mixture wasstirred at 80° C. for 16 hr under nitrogen atmosphere. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by thin layer chromatography (ethyl acetate/petroleum ether) togive the title compound (0.08 g).

¹H NMR (400 MHz, CDCl₃) δ 1.32 (3H, t, J=7.2 Hz), 4.25-4.34 (4H, m),5.34 (1H, d, J=17.6 Hz), 5.54 (1H, d, J=12.4 Hz), 6.46 (1H, t, J=2.0Hz), 6.94 (1H, dd, J=17.2, 11.2 Hz), 7.15 (2H, d, J=8.0 Hz), 7.36 (1H,s), 7.63 (2H, d, J=8.8 Hz), 7.71 (1H, d, J=1.6 Hz), 7.90 (1H, d, J=2.4Hz).

O)3-chloro-2-ethenyl-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoicacid

To a solution of methyl3-chloro-2-ethenyl-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoate(0.80 g) and ethyl3-chloro-2-ethenyl-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoate(0.80 g) in THF (5.08 mL)-water (5.08 mL) were added lithium hydroxidemonohydrate (0.20 g) and methanol (0.50 mL), and the mixture was stirredat 15° C. for 16 hr. The reaction mixture was poured into 1Nhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure to give the title compound (0.15g).

¹H NMR (400 MHz, CDCl₃) δ 4.28 (2H, s), 5.44 (1H, d, J=17.2 Hz), 5.59(1H, d, J=12.0 Hz), 6.49 (1H, t, J=2.0 Hz), 6.96 (1H, dd, J=18.0, 11.6Hz), 7.16 (2H, d, J=8.4 Hz), 7.51 (1H, s), 7.59 (2H, d, J=8.4 Hz), 7.80(1H, d, J=1.6 Hz), 7.90 (1H, d, J=2.4 Hz).

P)rac-3-chloro-2-ethenyl-N-(trans-2-hydroxycyclohexyl)-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzamide

To a solution of3-chloro-2-ethenyl-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoicacid (0.05 g), trans-2-aminocyclohexanol hydrochloride (0.03 g),1-hydroxybenzotriazole (0.03 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.04 g) indichloromethane (5.00 mL) was added triethylamine (0.04 g), and themixture was stirred for 16 hr. The reaction mixture was poured intowater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with 1N hydrochloric acid and saturated aqueous sodiumbicarbonate solution, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure to give the title compound(0.07 g).

¹H NMR (400 MHz, CDCl₃) δ 1.25-1.40 (4H, m), 1.70-1.77 (2H, m),1.90-2.00 (1H, m), 2.05-2.10 (1H, m), 3.32-3.40 (1H, m), 3.60-3.80 (1H,m), 4.26 (2H, s), 5.50-5.75 (3H, m), 6.45 (1H, t, J 2.0 Hz), 6.85-6.98(1H, m), 7.14 (2H, d, J=8.4 Hz), 7.30 (1H, s), 7.61 (2H, d, J=8.4 Hz),7.71 (1H, d, J=1.2 Hz), 7.89 (1H, d, J=2.4 Hz).

Q)rac-4-chloro-2-(trans-2-hydroxycyclohexyl)-6-(4-(1H-pyrazol-1-yl)benzyl)-5-(trifluoromethyl)isoindolin-1-one

To a solution ofrac-3-chloro-2-ethenyl-N-(trans-2-hydroxycyclohexyl)-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzamide(0.07 g) in a mixed solvent of acetone (2.00 mL)-acetonitrile (2.00mL)-water (2.00 ml) were added potassium osmate(VI) dihydrate (4.00 mg)and sodium periodate (0.08 g), and the mixture was stirred for 16 hr.The reaction mixture was diluted with aqueous sodium thiosulfatesolution, and the mixture was extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure to giverac-4-chloro-3-hydroxy-2-[trans-2-hydroxycyclohexyl]-6-[4-(1H-pyrazol-1-yl)benzyl]-5-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one(0.05 g) as a crude product. This compound was used in the next stepwithout an additional purification.

MS: [M+H]⁺ 505.9.

To a solution of the above-mentioned compound (0.05 g) indichloromethane (2.00 mL) was added trifluoroacetic acid (0.30 mL) underice-cooling. After 15 min, triethylsilane (0.40 mL) was added thereto,and the mixture was stirred at 15° C. for 16 hr. The reaction mixturewas poured into saturated aqueous sodium bicarbonate solution, and themixture was extracted with ethyl acetate (×2). The organic layer wasdried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by prep-HPLC, thenlyophilized to give the title compound (0.01 g).

¹H NMR (400 MHz, CDCl₃) δ 1.36-1.45 (2H, m), 1.54-1.62 (1H, m,overlapped with water signal), 1.83 (2H, d, J=12.0 Hz), 1.92 (1H, d,J=12.0 Hz), 2.13-2.26 (2H, m), 3.64-3.77 (1H, m), 4.03-4.13 (1H, m),4.33 (2H, s), 4.37-4.55 (2H, m), 6.45 (1H, t, J=2.0 Hz), 7.14 (2H, d,J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 7.64 (1H, s), 7.70 (1H, d, J=1.6 Hz),7.89 (1H, d, J=2.4 Hz).

Example 11rac-2-(trans-2-hydroxycyclohexyl)-4-methyl-1-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)isoindoline-5-carbonitrileA) 3-hydroxy-2-methylbenzonitrile

To a solution of 3-bromo-2-methylphenol (20.0 g) in DMF (250 mL) wereadded copper(I) cyanide (19.0 g) andtetrakis(triphenylphosphine)palladium(0) (3.70 g), and the mixture washeated with stirring at 120° C. for 16 hr under nitrogen atmosphere. Thereaction mixture was poured into water, and the mixture was filtered.The filtrate was extracted with ethyl acetate, and the organic layer wasdried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure, and the residue was washed with tert-butyl methylether to give the title compound (7.00 g).

¹H NMR (400 MHz, CDCl₃) δ 2.28 (3H, s), 7.00-7.15 (1H, m), 7.14-7.24(2H, m), 10.11 (1H, brs).

B) 4-formyl-3-hydroxy-2-methylbenzonitrile

To a solution of 3-hydroxy-2-methylbenzonitrile (7.00 g) in THF (100 mL)were added triethylamine (13.1 g), magnesium chloride (12.4 g) andparaformaldehyde (6.60 g), and the mixture was heated with reflux for 16hr under nitrogen atmosphere. The reaction mixture was poured into 1Nhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified by flashsilica gel column chromatography (ethyl acetate/petroleum ether) to givethe title compound (1.30 g).

¹H NMR (400 MHz, CDCl₃) δ 2.50 (3H, s), 7.24-7.28 (2H, m, overlappedwith CDCl₃ signal), 7.53 (1H, d, J=8.0 Hz), 9.98 (1H, s), 11.42 (1H,brs).

C) 4-cyano-2-hydroxy-3-methylbenzoic acid

To a solution of 4-formyl-3-hydroxy-2-methylbenzonitrile (3.90 g) inDMSO (21.0 mL) were added sodium dihydrogenphosphate (7.26 g) and anaqueous solution (16.0 mL) of sodium chlorite (5.46 g) underice-cooling, and the mixture was stirred at 17° C. for 16 hr. Thereaction mixture was poured into saturated aqueous sodium carbonatesolution, and the mixture was extracted with tert-butyl methyl ether.The aqueous layer was acidified with 1N hydrochloric acid, and themixture was extracted with ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure to give the title compound (4.00 g: containingDMSO).

¹H NMR (400 MHz, DMSO-d₆) δ 2.36 (3H, s), 7.29 (1H, d, J=8.0 Hz), 7.77(1H, d, J=8.0 Hz). An active proton was not observed.

D) 5-bromo-4-cyano-2-hydroxy-3-methylbenzoic acid

To a solution of 4-cyano-2-hydroxy-3-methylbenzoic acid (5.50 g) in DMF(50.0 mL) was added N-bromosuccinimide (5.50 g) under ice-cooling, andthe mixture was stirred at 15° C. for 16 hr. The reaction mixture waspoured into water, and the mixture was extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure to give the title compound (7.40g: containing DMF).

¹H NMR (400 MHz, CDCl₃) δ 2.51 (3H, s), 8.10 (1H, s), 11.48 (1H, brs).

E) methyl 5-bromo-4-cyano-2-hydroxy-3-methylbenzoate

To a solution of 5-bromo-4-cyano-2-hydroxy-3-methylbenzoic acid (7.40 g)in dichloromethane (70.0 mL) were added oxalyl chloride (3.91 g) and DMF(0.20 mL) under ice-cooling, and the mixture was stirred for 3 hr. Thereaction mixture was concentrated under reduced pressure, and theresidue was diluted with THF. To this mixture was added dropwise asolution of triethylamine (5.66 g) in methanol (50.0 mL) underice-cooling, and the mixture was stirred for 20 min. The reactionmixture was poured into 1N hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/petroleum ether) to give the title compound (4.20 g).

¹H NMR (400 MHz, CDCl₃) δ 2.51 (3H, s), 4.00 (3H, s), 7.97 (1H, s),10.14 (1H, brs).

F) methyl4-cyano-2-hydroxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

To a solution of methyl 5-bromo-4-cyano-2-hydroxy-3-methylbenzoate (2.00g) in toluene (30.0 mL) were added bis(pinacolato)diboron (2.82 g),potassium acetate (2.18 g) andtrans-dichlorobis(triphenylphosphine)palladium(II) (0.26 g), and themixture was stirred at 110° C. for 16 hr under argon atmosphere. Thereaction mixture was poured into water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by flash silica gelcolumn chromatography (ethyl acetate/petroleum ether) to give the titlecompound (2.50 g: containing bis(pinacolato)diboron).

¹H NMR (400 MHz, CDCl₃) δ 1.38 (12H, s), 2.49 (3H, s), 3.99 (3H, s),8.20 (1H, s), 11.43 (1H, brs).

G) methyl4-cyano-2-hydroxy-3-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate

To a solution of methyl4-cyano-2-hydroxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(3.50 g) in 1,4-dioxane (30.0 mL) were added1-(4-(chloromethyl)phenyl)-1H-pyrazole (2.12 g), tripotassium phosphatetrihydrate (5.90 g) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.34 g), and the mixture was stirred at 90° C.for 16 hr under nitrogen atmosphere. The reaction mixture was pouredinto water, and the mixture was extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified by flashsilica gel column chromatography (ethyl acetate/petroleum ether) to givethe title compound (0.86 g).

¹H NMR (400 MHz, CDCl₃) δ 2.49 (3H, s), 3.95 (3H, s), 4.15 (2H, s), 6.46(1H, s), 7.30 (2H, d, J=8.4 Hz), 7.59-7.60 (1H, m), 7.64 (2H, d, J=8.4Hz), 7.71 (1H, s), 7.90 (1H, d, J=2.4 Hz), 11.07 (1H, brs).

H) methyl4-cyano-3-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate

To a solution of methyl4-cyano-2-hydroxy-3-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate (0.86g) in THF (20.0 mL) was added sodium hydride (0.12 g) under ice-cooling,and the mixture was stirred for 20 min. To this reaction mixture wasadded N-phenylbis(trifluoromethanesulfonimide) (1.77 g), and the mixturewas stirred at 15° C. for 16 hr. The reaction mixture was poured intosaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure togive the title compound (3.00 g) as a crude product. This compound wasused in the next step without an additional purification.

MS: [M+H]⁺ 479.8.

I) methyl4-cyano-2-ethenyl-3-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate

To a solution of methyl4-cyano-3-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate(2.80 g) in THF (25.0 mL)-water (5.00 mL) were added potassiumvinyltrifluoroborate (0.85 g), cesium carbonate (6.23 g) andtetrakis(triphenylphosphine)palladium(0) (0.38 g), and the mixture wasstirred at 80° C. for 16 hr under nitrogen atmosphere. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by flash silica gel column chromatography (ethylacetate/petroleum ether) to give the title compound (0.80 g).

¹H NMR (400 MHz, CDCl₃) δ 2.56 (3H, s), 3.83 (3H, s), 4.23 (2H, s), 5.21(1H, d, J=17.6 Hz), 5.46-5.60 (1H, m), 6.46 (1H, s), 6.88 (1H, dd,J=17.6, 11.4 Hz), 7.32 (2H, d, J=8.4 Hz), 7.41 (1H, s), 7.64 (2H, d,J=8.4 Hz), 7.71 (1H, s), 7.90 (1H, d, J=2.4 Hz).

J) 4-cyano-2-ethenyl-3-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoic acid

To a solution of methyl4-cyano-2-ethenyl-3-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate (0.70g) in THF (5.00 mL)-water (5.00 mL) were added lithium hydroxidemonohydrate (0.25 g) and methanol (1.00 mL), and the mixture was stirredat 10° C. for 16 hr. The reaction mixture was diluted with water, andthe mixture was extracted with tert-butyl methyl ether. The aqueouslayer was acidified with 2N hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure togive the title compound (0.60 g).

¹H NMR (400 MHz, CDCl₃) δ 2.55 (3H, s), 4.22 (2H, s), 5.25 (1H, dd,J=17.8, 1.4 Hz), 5.55 (1H, dd, J=11.6, 1.2 Hz), 6.47 (1H, t, J=2.0 Hz),6.93 (1H, dd, J=17.8, 11.4 Hz), 7.34 (2H, d, J=8.4 Hz), 7.58 (1H, s),7.62 (2H, d, J=8.8 Hz), 7.79 (1H, d, J=1.6 Hz), 7.90 (1H, d, J=2.4 Hz).One active proton was not observed.

K)rac-4-cyano-2-ethenyl-N-(trans-2-hydroxycyclohexyl)-3-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzamide

To a solution of4-cyano-2-ethenyl-3-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoic acid(0.10 g), trans-2-aminocyclohexanol hydrochloride (0.06 g),1-hydroxybenzotriazole (0.06 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.08 g) indichloromethane (5.00 mL) was added triethylamine (0.11 g), and themixture was stirred for 16 hr. The reaction mixture was poured into 1Nhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with 1N hydrochloric acid and saturated aqueoussodium bicarbonate solution, and dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure to give the titlecompound (0.10 g).

¹H NMR (400 MHz, CDCl₃) δ 1.11-1.41 (6H, m), 1.95-2.10 (2H, m), 2.55(3H, s), 3.21-3.30 (1H, m), 3.36 (1H, td, J=10.0, 4.4 Hz), 3.68-3.80(1H, m), 4.20 (2H, s), 5.47 (1H, dd, J=17.8, 1.2 Hz), 5.61 (1H, dd,J=11.6, 1.2 Hz), 5.70 (1H, d, J=7.2 Hz), 6.45 (1H, t, J=2.0 Hz), 6.78(1H, dd, J=17.8, 11.6 Hz), 7.25-7.26 (1H, m, overlapped with CDCl₃signal), 7.32 (2H, d, J 8.4 Hz), 7.62 (2H, d, J=8.4 Hz), 7.70 (1H, d,J=2.0 Hz), 7.89 (1H, d, J=2.4 Hz).

L)rac-3-hydroxy-2-(trans-2-hydroxycyclohexyl)-4-methyl-1-oxo-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindole-5-carbonitrile

To a solution ofrac-4-cyano-2-ethenyl-N-(trans-2-hydroxycyclohexyl)-3-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzamide(0.09 g) in a mixed solvent of acetone (2.00 mL)-acetonitrile (2.00mL)-water (2.00 mL) were added potassium osmate(VI) dihydrate (7.00 mg)and sodium periodate (0.18 g), and the mixture was stirred for 16 hr.The reaction mixture was diluted with saturated aqueous sodiumthiosulfate solution, and the mixture was extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure to give the title compound(0.10 g) as a crude product. This compound was used in the next stepwithout an additional purification.

MS: [M+H]⁺ 443.0.

M)rac-2-(trans-2-hydroxycyclohexyl)-4-methyl-1-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)isoindoline-5-carbonitrile

To a solution ofrac-3-hydroxy-2-(trans-2-hydroxycyclohexyl)-4-methyl-1-oxo-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindole-5-carbonitrile(0.10 g) in dichloromethane (2.00 mL) was added trifluoroacetic acid(0.31 mL) under ice-cooling. After 15 min, triethylsilane (0.50 mL) wasadded thereto, and the mixture was stirred at 15° C. for 16 hr. Thereaction mixture was poured into saturated aqueous sodium bicarbonatesolution, and the mixture was extracted with ethyl acetate (×2). Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified byprep-HPLC, then lyophilized to give the title compound (0.02 g).

¹H NMR (400 MHz, CDCl₃) δ 1.35-1.52 (3H, m), 1.85 (2H, d, J=12.4 Hz),1.94 (1H, d, J=13.6 Hz), 2.10 (1H, d, J=6.8 Hz), 2.20 (1H, d, J=12.0Hz), 2.57 (3H, s), 3.55-3.65 (1H, m), 4.07-4.16 (1H, m), 4.30-4.48 (4H,m), 6.41-6.51 (1H, m), 7.35 (2H, d, J=8.4 Hz), 7.61-7.69 (3H, m), 7.72(1H, d, J=1.6 Hz), 7.91 (1H, d, J=2.4 Hz). One active proton wasobserved.

Example 12rac-4-chloro-2-(trans-2-hydroxycyclohexyl)-5-methoxy-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-oneA) 2-chloro-3-methoxyphenol

To an aqueous solution (100 mL) of potassium hydroxide (11.0 g) wasadded 2-chlorobenzene-1,3-diol (22.8 g). Then, dimethyl sulfate (19.9 g)was slowly added to the reaction mixture while keeping the reactionmixture at 10° C. to 20° C., and the mixture was stirred at 100° C. for2 days. The reaction mixture was acidified with 2N hydrochloric acid,and the mixture was extracted with dichloromethane. The organic layerwas dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to give the titlecompound (18.0 g).

¹H NMR (400 MHz, DMSO-d₆) δ 3.78 (3H, s), 6.54-6.58 (2H, m), 7.05 (1H,t, J=8.4 Hz), 10.04 (1H, brs).

B) 3-chloro-2-hydroxy-4-methoxybenzaldehyde

To a solution of 2-chloro-3-methoxyphenol (19.3 g) in 1,2-dichloroethane(150 mL) were added triethylamine (73.7 g), magnesium chloride (57.8 g)and paraformaldehyde (36.5 g), and the mixture was stirred at 70° C. for4 hr under nitrogen atmosphere. The reaction mixture was poured into 1Nhydrochloric acid, and the precipitate was removed by filtration, andwashed with dichloromethane. The organic layer was washed with 1Nhydrochloric acid and saturated brine, and dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure to givethe title compound (21.5 g).

¹H NMR (400 MHz, DMSO-d₆) δ 3.97 (3H, s), 6.92 (1H, d, J=8.8 Hz), 7.76(1H, d, J=9.2 Hz), 9.95 (1H, s), 11.47 (1H, brs).

C) 3-chloro-2-hydroxy-4-methoxybenzoic acid

To a solution of 3-chloro-2-hydroxy-4-methoxybenzaldehyde (16.6 g) andsodium dihydrogenphosphate (34.7 g) in a mixed solvent of DMSO (180mL)-water (45.0 mL) was added an aqueous solution (35.0 mL) of sodiumchlorite (27.2 g) under ice-cooling, and the mixture was stirred at 15°C. for 16 hr. The reaction mixture was poured into saturated aqueoussodium carbonate solution, the mixture was diluted with water, andfiltered, and the filtrate was extracted with petroleum ether/ethylacetate=5:1. The aqueous layer was acidified with conc. hydrochloricacid to adjusted pH=1, and the mixture was extracted with ethyl acetate.The organic layer was washed with 1N hydrochloric acid, and dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure to give the title compound (11.1 g).

¹H NMR (400 MHz, DMSO-d₆) δ3.93 (3H, s), 6.77 (1H, d, J=9.2 Hz), 7.78(1H, d, J=9.2 Hz), 12.11 (1H, brs). One active proton was not observed.

D) 5-bromo-3-chloro-2-hydroxy-4-methoxybenzoic acid

To a solution of 3-chloro-2-hydroxy-4-methoxybenzoic acid (11.1 g) inacetic acid (275 mL) was added bromine (8.79 g) at room temperature, andthe mixture was stirred for 16 hr. To the reaction mixture was addedwater, and the precipitate was collected by filtration. The precipitatewas washed with water, and dissolved in ethyl acetate, and the solutionwas washed with water and saturated brine. The organic layer was driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure to give the title compound (10.4 g).

¹H NMR (400 MHz, DMSO-d₆) δ3.87 (3H, s), 7.94 (1H, s). Two activeprotons were not observed.

E) methyl 5-bromo-3-chloro-2-hydroxy-4-methoxybenzoate

To a solution of 5-bromo-3-chloro-2-hydroxy-4-methoxybenzoic acid (10.4g) in dichloromethane (150 mL) were added a solution of oxalyl chloride(7.05 g) in dichloromethane (10 mL) and DMF (3 drops) under ice-cooling,and the mixture was stirred at 13° C. for 1 hr. The solvent wasevaporated under reduced pressure, and the residue was dissolved in THF(50 mL). This solution was added dropwise to a solution of triethylamine(1.20 g) in methanol (150 mL) under ice-cooling, and the mixture wasstirred at 13° C. for 16 hr. The solvent was evaporated under reducedpressure from the reaction mixture, and the residue was diluted withethyl acetate and water. 1N Hydrochloric acid was added thereto, and themixture was partitioned. The organic layer was washed with water andsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure to give the title compound(10.9 g).

¹H NMR (400 MHz, DMSO-d₆) δ3.86 (3H, s), 3.91 (3H, s), 7.94 (1H, s),11.11 (1H, brs).

F) methyl 5-bromo-3-chloro-4-methoxy-2-(methoxymethoxy)benzoate

To a solution of methyl 5-bromo-3-chloro-2-hydroxy-4-methoxybenzoate(5.00 g) in THF (120 mL) was added sodium hydride (1.01 g) underice-cooling, and the mixture was stirred for 1 hr under nitrogenatmosphere. To this reaction mixture was added dropwise chloromethylmethyl ether (1.63 g), and the mixture was stirred at 20° C. for 16 hr.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by flash silica gelcolumn chromatography (ethyl acetate/petroleum ether) to give the titlecompound (3.08 g).

¹H NMR (400 MHz, CDCl₃) δ 3.65 (3H, s), 3.93 (3H, s), 3.96 (3H, s), 5.15(2H, s), 8.00 (1H, s).

G)1-{4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]phenyl}-1H-pyrazole

To a solution of 1-[4-(chloromethyl)phenyl]-1H-pyrazole (2.20 g) in1,4-dioxane (50.0 mL) were added bis(pinacolato)diboron (3.47 g),potassium acetate (3.35 g) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.47 g), and the mixture was stirred at 90° C.for 16 hr under argon atmosphere. The reaction mixture was allowed to becooled to room temperature, and filtered, and the solvent was evaporatedunder reduced pressure from the filtrate. The residue was purified bysilica gel column chromatography (ethyl acetate/petroleum ether) to givethe title compound (3.10 g).

¹HNMR (400 MHz, CDCl₃) δ 1.22 (12H, s), 2.32 (2H, s), 6.43 (1H, t, J=2.0Hz), 7.23-7.29 (2H, m, overlap with CDCl₃ signal), 7.54 (2H, d, J=8.4Hz), 7.69 (1H, d, J=1.2 Hz), 7.87 (1H, d, J=2.8 Hz).

H) methyl3-chloro-2-hydroxy-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate

To a solution of methyl5-bromo-3-chloro-4-methoxy-2-(methoxymethoxy)benzoate (3.00 g) in1,4-dioxane (50.0 mL)-water (5.00 mL) were added1-{4-[(4,4,5,5-tetramerthyl-1,3,2-dioxaborolan-2-yl)methyl]phenyl}-1H-pyrazole(7.50 g), potassium carbonate (2.44 g) andtetrakis(triphenylphosphine)palladium(0) (1.02 g), and the mixture wasstirred at 90° C. for 16 hr under nitrogen atmosphere. The reactionmixture was poured into water, and the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by flash silica gel column chromatography (ethylacetate/petroleum ether) to give methyl3-chloro-4-methoxy-2-(methoxymethoxy)-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate(0.40 g).

To a solution of the above-mentioned compound (0.40 g) in ethyl acetate(5.00 mL) was added 4N hydrogen chloride/ethyl acetate (25.0 mL), andthe mixture was stirred at room temperature for 16 hr. The reactionmixture was poured into saturated aqueous sodium bicarbonate solution,and the mixture was extracted with ethyl acetate. The organic layer wasdried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by flash silica gelcolumn chromatography (ethyl acetate/petroleum ether) to give the titlecompound (0.23 g).

¹H NMR (400 MHz, CDCl₃) δ 3.78 (3H, s), 3.93 (3H, s), 3.97 (2H, s), 6.45(1H, t, J=2.0 Hz), 7.24 (1H, s), 7.27 (1H, s, overlapped with CDCl₃signal), 7.58-7.63 (3H, m), 7.71 (1H, d, J=1.6 Hz), 7.89 (1H, d, J=2.4Hz), 11.36 (1H, brs).

I) methyl3-chloro-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate

To a solution of methyl3-chloro-2-hydroxy-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate (0.23g) in dichloromethane (10.0 mL) were added triethylamine (0.13 g) andtrifluoromethanesulfonic anhydride (0.35 g) under ice-cooling, and themixture was stirred at room temperature for 16 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure to give the titlecompound (0.36 g) as a crude product. This compound was used in the nextstep without an additional purification.

MS: [M+H]⁺ 505.0.

J) methyl3-chloro-2-ethenyl-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate

To a solution of methyl3-chloro-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate(0.36 g) in THF (8.00 mL)-water (3.00 mL) were added potassiumvinyltrifluoroborate (0.17 g), cesium carbonate (0.60 g) andtetrakis(triphenylphosphine)palladium(0) (0.04 g), and the mixture washeated with reflux for 16 hr under nitrogen atmosphere. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by thin layer chromatography (ethyl acetate/petroleum ether) togive the title compound (0.08 g).

¹H NMR (400 MHz, CDCl₃) δ 3.76 (3H, s), 3.81 (3H, s), 4.05 (2H, s), 5.33(1H, d, J=17.6 Hz), 5.52 (1H, dd, J=11.2, 1.2 Hz), 6.45 (1H, t, J=2.0Hz), 6.93 (1H, dd, J=17.8, 11.2 Hz), 7.28 (2H, d, J=8.4 Hz), 7.43 (1H,s), 7.62 (2H, d, J=8.4 Hz), 7.71 (1H, d, J=1.4 Hz), 7.89 (1H, d, J=2.4Hz).

K) 3-chloro-2-ethenyl-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoicacid

To a solution of methyl3-chloro-2-ethenyl-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate (0.10g) in THF (3.00 mL)-water (3.00 mL) and methanol (0.50 mL) was addedlithium hydroxide monohydrate (0.10 g), and the mixture was stirred at20° C. for 16 hr. The reaction mixture was poured into 1N hydrochloricacid, and the mixture was extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure to give the title compound (0.08 g).

¹H NMR (400 MHz, CDCl₃) δ 3.78 (3H, s), 4.22 (2H, s), 4.06 (2H, s), 5.42(1H, d, J=17.6 Hz), 5.58 (1H, d, J=11.2 Hz), 6.46 (1H, t, J=2.0 Hz),6.94 (1H, dd, J=18.0, 11.6 Hz), 7.25-7.40 (2H, m, overlap with CDCl₃signal), 7.50-7.65 (3H, m), 7.72 (1H, s), 7.89 (1H, d, J=2.4 Hz). Anactive proton was not observed.

L)rac-3-chloro-2-ethenyl-N-(trans-2-hydroxycyclohexyl)-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzamide

To a solution of3-chloro-2-ethenyl-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoic acid(0.06 g), trans-2-aminocyclohexanol hydrochloride (0.04 g),1-hydroxybenzotriazole (0.03 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.05 g) indichloromethane (10.0 mL) was added triethylamine (0.03 g), and themixture was stirred at room temperature for 16 hr. The reaction mixturewas poured into water, and the mixture was extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure to give the title compound(0.08 g).

¹H NMR (400 MHz, CDCl₃) δ 1.31-1.39 (3H, m), 1.70-1.76 (2H, m),1.97-2.12 (3H, m), 3.23 (1H, brs), 3.30-3.40 (1H, m), 3.65-3.75 (4H, m),4.03 (2H, s), 5.56-5.65 (2H, m), 5.69 (1H, d, J=7.6 Hz), 6.45 (1H, t,J=2.0 Hz), 6.88 (1H, dd, J=18.0, 11.2 Hz), 7.27-7.30 (2H, m, overlappedwith CDCl₃ signal), 7.61 (2H, d, J=8.4 Hz), 7.70 (1H, d, J=1.6 Hz), 7.89(1H, d, J=2.0 Hz).

M)rac-4-chloro-3-hydroxy-2-(trans-2-hydroxycyclohexyl)-5-methoxy-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindol-1-one

To a solution ofrac-3-chloro-2-ethenyl-N-(trans-2-hydroxycyclohexyl)-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzamide(0.08 g) in a mixed solvent of acetone (2.00 mL)-acetonitrile (2.00mL)-water (2.00 mL) were added potassium osmate(VI) dihydrate (5.00 mg)and sodium periodate (0.12 g), and the mixture was stirred at roomtemperature for 16 hr. The reaction mixture was diluted with saturatedaqueous sodium thiosulfate solution, and the mixture was extracted withethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure to givethe title compound (0.07 g) as a crude product. This compound was usedin the next step without an additional purification.

MS: [M+Na]⁺ 450.1.

N)rac-4-chloro-2-(trans-2-hydroxycyclohexyl)-5-methoxy-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-one

To a solution ofrac-4-chloro-3-hydroxy-2-(trans-2-hydroxycyclohexyl)-5-methoxy-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindol-1-one(0.07 g) in dichloromethane (2.00 mL) was added trifluoroacetic acid(0.50 mL) under ice-cooling, and the mixture was stirred for 15 min.Then, triethylsilane (0.40 mL) was added thereto, and the mixture wasstirred at room temperature for 1 hr. The reaction mixture was pouredinto saturated aqueous sodium bicarbonate solution, and the mixture wasextracted with ethyl acetate (×2). The organic layer was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by prep-HPLC, then lyophilized togive the title compound (0.02 g).

¹H NMR (400 MHz, CDCl₃) δ 1.35-1.45 (3H, m), 1.50-1.60 (1H, m,overlapped with water signal), 1.81 (2H, d, J=12.0 Hz), 1.91 (1H, d,J=12.0 Hz), 2.13-2.33 (2H, m), 3.60-3.70 (1H, m), 3.78 (3H, s),4.03-4.12 (3H, m), 4.37 (2H, q, J=17.2 Hz), 6.44 (1H, t, J=2.0 Hz),7.20-7.30 (2H, m, overlapped with CDCl₃ signal), 7.57-7.62 (3H, m), 7.70(1H, d, J=1.2 Hz), 7.88 (1H, d, J=2.4 Hz).

Example 132-((1S,2S)-2-hydroxycyclopentyl)-4,5-dimethyl-6-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)isoindolin-1-oneA) 1-methyl-1H-pyrazol-3-yl trifluoromethanesulfonate

To a solution of 1-methyl-1H-pyrazol-3-ol (2.92 g) in pyridine (50.0 mL)was added trifluoromethanesulfonic anhydride (6.03 mL) underice-cooling, and the mixture was stirred for 1 hr. The reaction mixturewas diluted with saturated aqueous sodium bicarbonate solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (5.44 g).

¹H NMR (300 MHz, CDCl₃) δ 3.87 (3H, s), 6.11 (1H, d, J=2.3 Hz), 7.32(1H, d, J=2.3 Hz).

B) [4-(1-methyl-1H-pyrazol-3-yl)phenyl]methanol

A mixture of [4-(hydroxymethyl)phenyl]boronic acid (4.46 g),1-methyl-1H-pyrazol-3-yl trifluoromethanesulfonate (4.50 g), cesiumcarbonate (19.1 g) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.80 g) in toluene (15.0 mL)-ethanol (1.00mL)-water (1.00 mL) was subjected to microwave irradiation at 150° C.for 1 hr. The reaction mixture was diluted with ethyl acetate, and theinsoluble substance was removed by filtration. The filtrate was washedsuccessively with saturated aqueous sodium bicarbonate solution andsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (1.00 g).

¹H NMR (300 MHz, CDCl₃) δ 3.95 (3H, s), 4.71 (2H, d, J=6.0 Hz), 6.54(1H, d, J=2.3 Hz), 7.33-7.45 (1H, m), 7.73-7.87 (1H, m).

C) 3-[4-(chloromethyl)phenyl]-1-methyl-1H-pyrazole

To a solution of [4-(1-methyl-1H-pyrazol-3-yl)phenyl]methanol (1.00 g)in THF (15.0 mL) was added dropwise thionyl chloride (0.58 mL) underice-cooling, and the mixture was stirred at 17° C. for 16 hr. Thereaction mixture was diluted with water and ethyl acetate, and saturatedaqueous sodium bicarbonate was added thereto. The organic layer waswashed with saturated brine, and dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.65 g).

¹H NMR (300 MHz, CDCl₃) δ 3.95 (3H, s), 4.61 (2H, s), 6.49-6.57 (1H, m),7.33-7.44 (3H, m), 7.74-7.82 (2H, m).

D) 2-amino-5-bromo-3,4-dimethylbenzoic acid

To a solution of 2-amino-3,4-dimethylbenzoic acid (50.0 g) in DMSO (500mL) was added hydrobromic acid (174 mL) while keeping the internaltemperature at 25 to 30° C., and the mixture was stirred overnight atroom temperature. To the reaction mixture was added water (500 mL), andthe mixture was stirred for 30 min. The precipitate was collected byfiltration, and washed with water to give the title compound (102 g:containing DMSO).

MS: [M−H]⁺ 241.9.

E) methyl 2-amino-5-bromo-3,4-dimethylbenzoate

To a solution of 2-amino-5-bromo-3,4-dimethylbenzoic acid (73.9 g) inDMF (750 mL) was added cesium carbonate (148 g), and the mixture wasstirred at room temperature for 30 min. To this reaction mixture wasadded dropwise methyl iodide (22.7 mL) at room temperature, and themixture was stirred overnight. To the reaction mixture was added water,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (56.8 g).

MS: [M+H]⁺ 258.1.

F) methyl 5-bromo-2-hydroxy-3,4-dimethylbenzoate

To an aqueous solution (160 mL) of methyl2-amino-5-bromo-3,4-dimethylbenzoate (28.0 g) in 25% sulfuric acid wasadded dropwise an aqueous solution (80.0 mL) of sodium nitrite (11.2 g)over 50 min at the internal temperature of 2-3° C. under ice-cooling.Then, 5% aqueous sulfuric acid solution (1600 mL) was added dropwisethereto over 50 min at 0-15° C. The reaction mixture was stirred at 100°C. for 2 hr. The reaction mixture was allowed to be cooled to roomtemperature, and the precipitate was collected by filtration, and washedwith water to give the title compound (25.7 g).

MS: [M−H]⁺ 256.9.

G) methyl2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

To a solution of methyl 5-bromo-2-hydroxy-3,4-dimethylbenzoate (25.7 g)in toluene (500 mL) were added bis(pinacolato)diboron (37.8 g),potassium acetate (29.2 g) andtrans-dichlorobis(triphenylphosphine)palladium(II) (0.70 g), and themixture was stirred under argon atmosphere at 100° C. for 2 hr. To thereaction mixture was again addedtrans-dichlorobis(triphenylphosphine)palladium(II) (0.70 g), and the somixture was stirred overnight at 100° C. The reaction mixture wasallowed to be cooled to room temperature, water was added thereto, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was collected by filtration, and washed with ethylacetate to give the title compound (18.3 g).

MS: [M−H]⁺ 305.1.

H) methyl2-hydroxy-3,4-dimethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)benzoate

To a solution of methyl2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(0.97 g), 3-[4-(chloromethyl)phenyl]-1-methyl-1H-pyrazole (0.65 g) andsodium carbonate (0.67 g) in a mixed solvent of 1,2-dimethoxyethane(12.0 mL)-water (4.00 mL) was addedtetrakis(triphenylphosphine)palladium(0) (0.18 g) under argonatmosphere, and the mixture was stirred overnight at 80° C. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.65g).

¹H NMR (300 MHz, CDCl₃) δ 2.14 (3H, s), 2.20 (3H, s), 3.91 (3H, s), 3.94(3H, s), 3.97 (2H, s), 6.49 (1H, d, J=2.3 Hz), 7.10 (2H, d, J=8.3 Hz),7.35 (1H, d, J=2.3 Hz), 7.53 (1H, s), 7.65-7.72 (2H, m), 10.99 (1H, s).

I) methyl3,4-dimethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl2-hydroxy-3,4-dimethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)benzoate(1.00 g) in DMF (12.0 mL) were added sodium hydride (0.14 g) andN-phenylbis(trifluoromethanesulfonimide) (1.12 g) under ice-cooling, andthe mixture was stirred for 2 hr. To the reaction mixture was added 1Nhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium bicarbonatesolution and saturated brine, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (1.30 g).

¹H NMR (300 MHz, CDCl₃) δ 2.21 (3H, s), 2.30 (3H, s), 3.91 (3H, s), 3.94(3H, s), 4.05 (2H, s), 6.50 (1H, d, J=2.3 Hz), 7.10 (1H, d, J=8.1 Hz),7.36 (1H, d, J=2.3 Hz), 7.65-7.74 (1H, m).

J) methyl3,4-dimethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-vinylbenzoate

A solution of methyl3,4-dimethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate(1.30 g), tributylvinyltin (1.28 g),trans-dichlorobis(triphenylphosphine)palladium(II) (0.10 g) and lithiumchloride (0.80 g) in DMF (12.0 mL) was stirred at 90° C. for 2 hr underargon atmosphere. To the reaction mixture was added aqueous potassiumfluoride solution, and the precipitated insoluble substance was removedby filtration through Celite. The filtrate was diluted with ethylacetate, and the mixture was washed with water and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.96 g).

¹H NMR (300 MHz, CDCl₃) δ 2.17 (3H, s), 2.26 (3H, s), 3.81 (3H, s), 3.94(3H, s), 4.04 (2H, s), 5.11 (1H, dd, J=17.8, 1.9 Hz), 5.44 (1H, dd,J=11.2, 1.8 Hz), 6.49 (1H, d, J=2.3 Hz), 7.04 (1H, dd, J=17.8, 11.3 Hz),7.12 (2H, d, J=8.5 Hz), 7.32-7.39 (2H, m), 7.44 (1H, s), 7.65-7.72 (1H,m).

K) methyl2-formyl-3,4-dimethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)benzoate

To a solution of methyl3,4-dimethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-vinylbenzoate(0.96 g) in a mixed solvent of acetone (10.0 mL)-acetonitrile (10.0mL)-water (10.0 mL) were added osmium oxide (fixed catalyst I) (0.34 g)and sodium periodate (2.86 g), and the mixture was stirred overnight atroom temperature. The reaction mixture was concentrated under reducedpressure, and the residue was diluted with ethyl acetate and water. Theinsoluble substance was removed by filtration, and the filtrate waswashed with saturated aqueous sodium bicarbonate solution, water andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.17 g).

MS: [M+H]⁺ 363.2.

L)2-((1S,2S)-2-hydroxycyclopentyl)-4,5-dimethyl-6-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)isoindolin-1-one

A solution of methyl2-formyl-3,4-dimethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)benzoate(0.09 g), (1S,2S)-2-aminocyclopentanol hydrochloride (0.03 g),triethylamine (0.03 mL) and anhydrous magnesium sulfate (0.06 g) in THF(1.80 mL) was stirred at room temperature for 46 hr under nitrogenatmosphere. The insoluble substance was removed by filtration, and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with methanol (1.80 mL) and THF (1.80 mL), sodiumtriacetoxyborohydride (0.10 g) was added thereto, and the mixture wasstirred at room temperature for 7.5 hr. The reaction mixture was dilutedwith ethyl acetate, and the mixture was washed with water and saturatedbrine. The organic layer was dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.04 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.47-1.77 (4H, m), 1.81-1.97 (2H, m), 2.20(3H, s), 2.23 (3H, s), 3.86 (3H, s), 4.07-4.30 (4H, m), 4.39 (2H, s),4.89 (1H, d, J=4.9 Hz), 6.61 (1H, d, J=2.3 Hz), 7.12 (2H, d, J=7.9 Hz),7.33 (1H, s), 7.65-7.71 (3H, m).

Example 144,5-dimethyl-6-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2-((2S)-tetrahydrofuran-2-ylmethyl)isoindolin-1-oneA) [4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]methanol

A mixture of [4-(hydroxymethyl)phenyl]boronic acid (7.10 g),4-bromo-1-methyl-1H-1,2-3-triazole (5.00 g), sodium carbonate (6.59 g)and tetrakis(triphenylphosphine)palladium(0) (3.59 g) in a mixed solventof water (30.0 mL)-1,4-dioxane (100 mL) was heated with reflux for 16 hrunder nitrogen atmosphere. The reaction mixture was allowed to be cooledto room temperature, the organic layer was concentrated under reducedpressure, and the residue was extracted with dichloromethane (×3). Thecombined extracts were dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/petroleum ether) togive the title compound (3.40 g).

MS: [M+H]⁺ 189.9.

B) 4-[4-(bromomethyl)phenyl]-1-methyl-1H-1,2,3-triazole

To a solution of [4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]methanol(3.40 g) in dichloromethane (130 mL) was added dropwise phosphorustribromide (23.0 g) under ice-cooling, and the mixture was stirred at20° C. for 16 hr. The reaction mixture was concentrated under reducedpressure, the residue was poured into saturated aqueous sodiumbicarbonate solution, and the mixture was extracted with dichloromethane(×3). The combined organic layers were washed with water and saturatedbrine, and dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/petroleum ether) to give thetitle compound (3.50 g) as a mixture with phosphine oxide. This mixturewas diluted with tert-butyl methyl ether, and the mixture was stirred at20° C. for 16 hr. The precipitate was collected by filtration, and driedunder reduced pressure to give the title compound (3.40 g).

MS: [M+H]⁺ 251.8.

C) methyl2-hydroxy-3,4-dimethyl-5-(4-(1-methyl-H-1,2,3-triazol-4-yl)benzyl)benzoate

To a mixture of methyl2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(0.76 g), 4-[4-(bromomethyl)phenyl]-1-methyl-1H-1,2,3-triazole (0.63 g)and sodium carbonate (0.53 g) in 1,2-dimethoxyethane (12.0 mL)-water(4.00 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.29 g),and the mixture was stirred overnight at 80° C. under argon atmosphere.To the reaction mixture were added water and ethyl acetate, and themixture was partitioned. The organic layer was washed with water andsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.60 g).

MS: [M+H]⁺ 352.2.

D) methyl3,4-dimethyl-5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl2-hydroxy-3,4-dimethyl-5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)benzoate(0.60 g) in DMF (12.0 mL) were added sodium hydride (0.08 g) andN-phenylbis(trifluoromethanesulfonimide) (0.67 g) under ice-cooling, andthe mixture was stirred for 2 hr. To the reaction mixture was added 1Nhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium bicarbonatesolution and saturated brine, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.60 g).

MS: [M+H]⁺ 484.1.

E) methyl3,4-dimethyl-5-(4-(1-methyl-H-1,2,3-triazol-4-yl)benzyl)-2-vinylbenzoate

To a solution of methyl3,4-dimethyl-5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate(0.60 g) in DMF (12.0 mL) were added tributylvinyltin (1.28 g),trans-dichlorobis(triphenylphosphine)palladium(II) (0.10 g) and lithiumchloride (0.80 g), and the mixture was stirred at 90° C. for 1.5 hrunder argon atmosphere. To the reaction mixture was added aqueouspotassium fluoride solution, and the precipitated insoluble substancewas removed by filtration through Celite. The filtrate was diluted withethyl acetate, and the mixture was washed with water and saturatedbrine. The organic layer was dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.42 g).

MS: [M+H]⁺ 362.2.

F) methyl2-formyl-3,4-dimethyl-5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)benzoate

To a solution of methyl3,4-dimethyl-5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2-vinylbenzoate(0.42 g) in a mixed solvent of acetone (10.0 mL)-acetonitrile (10.0mL)-water (10.0 mL) were added osmium oxide (fixed catalyst I) (0.15 g)and sodium periodate (1.24 g), and the mixture was stirred overnight atroom temperature. The reaction mixture was filtered, and the filtratewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure to give the titlecompound (0.26 g) as a crude product.

MS: [M+H]⁺ 364.2.

G)3-hydroxy-4,5-dimethyl-6-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2-(((2S)-tetrahydrofuran-2-yl)methyl)isoindolin-1-one

To a solution of methyl2-formyl-3,4-dimethyl-5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)benzoate(0.13 g) in THF (3.00 mL) were added1-((2S)-tetrahydrofuran-2-yl)methanamine (0.04 mL) and anhydrousmagnesium sulfate (0.04 g), and the mixture was stirred overnight atroom temperature. The reaction mixture was diluted with ethyl acetate,and the mixture was washed with water and saturated brine. The organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.11 g).

MS: [M+H]⁺ 433.3.

H)4,5-dimethyl-6-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2-((2S)-tetrahydrofuran-2-ylmethyl)isoindolin-1-one

To a solution of3-hydroxy-4,5-dimethyl-6-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-2-(((2S)-tetrahydrofuran-2-yl)methyl)isoindolin-1-one(0.11 g) in trifluoroacetic acid (1.50 mL) was added triethylsilane(0.08 mL), and the mixture was stirred at room temperature for 15 min.The reaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.08 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.49-1.62 (1H, m), 1.74-1.98 (3H, m), 2.21(6H, s), 3.45-3.56 (1H, m), 3.57-3.68 (2H, m), 3.74-3.84 (1H, m),4.01-4.14 (6H, m), 4.39-4.54 (2H, m), 7.19 (2H, d, J=7.9 Hz), 7.34 (1H,s), 7.73 (2H, d, J=8.3 Hz), 8.44 (1H, s).

Example 152-(2-hydroxy-2-methylpropyl)-4,5-dimethyl-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-oneA) methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-hydroxy-3,4-dimethylbenzoate

To a solution of methyl2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(0.60 g) in DME (12.0 mL) were added1-(4-(bromomethyl)phenyl)-1H-pyrazole (0.51 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.08 g) and 2 mol/L aqueous sodium carbonatesolution (1.96 mL), and the mixture was stirred overnight at 80° C.under argon atmosphere. The reaction mixture was allowed to be cooled toroom temperature, water and ethyl acetate were added thereto, and themixture was partitioned. The organic layer was washed with water andsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.54 g).

MS: [M+H]⁺ 337.2.

B) methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-3,4-dimethyl-2-vinylbenzoate

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-2-hydroxy-3,4-dimethylbenzoate (0.54 g) inDMF (10 mL) was added sodium hydride (0.08 g) under ice-cooling, and themixture was stirred for 30 min. To this reaction mixture was addedN-phenylbis(trifluoromethanesulfonimide) (0.63 g), and the mixture wasstirred at room temperature for 1 hr. To the reaction mixture was added1N hydrochloric acid, and the mixture was extracted with ethyl acetate.The organic layer was washed with water and saturated brine, and driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained crude methyl3,4-dimethyl-5-[4-(1H-pyrazol-1-yl)benzyl]-2-{[(trifluoromethyl)sulfonyl]oxy}benzoatewas used in the next step without an additional purification.

MS: [M+H]⁺ 469.1.

The above-mentioned compound was dissolved in DMF (10 mL),tributylvinyltin (0.71 mL),trans-dichlorobis(triphenylphosphine)palladium(II) (0.06 g) and lithiumchloride (0.50 g) were added thereto, and the mixture was stirredovernight at 90° C. under argon atmosphere. To the reaction mixture wasagain added trans-dichlorobis(triphenylphosphine)palladium(II) (0.11 g),and the mixture was stirred at 90° C. for 2 hr under argon atmosphere.To the reaction mixture was added aqueous potassium fluoride solution,and the precipitated insoluble substance was removed by filtrationthrough Celite. The filtrate was diluted with ethyl acetate, and themixture was washed with water and saturated brine. The organic layer wasdried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.19g).

MS: [M+H]⁺ 347.2.

C) methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-3,4-dimethylbenzoate

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3,4-dimethyl-2-vinylbenzoate (0.40 g) in amixed solvent of acetone (8.00 mL)-acetonitrile (8.00 mL)-water (8.00mL) were added osmium oxide (fixed catalyst I) (0.15 g) and sodiumperiodate (1.24 g), and the mixture was stirred overnight at roomtemperature. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. To the residue was added water, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (0.11 g).

MS: [M+H]⁺ 349.1.

D)2-(2-hydroxy-2-methylpropyl)-4,5-dimethyl-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-one

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-3,4-dimethylbenzoate (0.11 g) inTHF (4.00 mL) was added 1-amino-2-methylpropan-2-ol (0.03 g), and themixture was stirred at room temperature for 2 hr. The reaction mixturewas concentrated, and the residue was diluted with methanol (4.0 mL).Sodium triacetoxyborohydride (0.11 g) was added thereto under argonatmosphere, and the mixture was stirred overnight at room temperature.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby NH silica gel column chromatography (ethyl acetate/hexane) to givethe title compound (0.04 g).

¹H NMR (300 MHz, CDCl₃) δ 1.31 (6H, s), 2.23 (3H, s), 2.26 (3H, s), 3.27(1H, s), 3.63 (2H, s), 4.13 (2H, s), 4.51 (2H, s), 6.43-6.47 (1H, m),7.19 (2H, d, J=8.5 Hz), 7.56-7.62 (3H, m), 7.71 (1H, d, J=1.5 Hz), 7.88(1H, d, J=2.5 Hz).

Example 166-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-2-((1S,2S)-2-hydroxycyclopentyl)-4,5-dimethylisoindolin-1-oneA) methyl 2-fluoro-4-(1H-pyrazol-1-yl)benzoate

To a solution of (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (2.40g) and 1H-pyrazole (0.99 g) in methanol (54.0 mL) was added copper(I)oxide (0.10 g), and the mixture was stirred overnight at 50° C. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.89 g).

MS: [M+H]⁺ 221.1.

B) (2-fluoro-4-(1H-pyrazol-1-yl)phenyl)methanol

To a solution of lithium aluminium hydride (0.16 g) in THF (5.50 mL) wasadded a solution of methyl 2-fluoro-4-(1H-pyrazol-1-yl)benzoate (0.89 g)in THF (5.50 mL) under ice-cooling, and the mixture was stirred for 1hr. To the reaction solution was added water, the insoluble substancewas removed by filtration, and the filtrate was concentrated underreduced pressure to give the title compound (0.71 g) as a crude product.

MS: [M+H]⁺ 193.1.

C) 1-(4-(chloromethyl)-3-fluorophenyl)-1H-pyrazole

To a solution of (2-fluoro-4-(1H-pyrazol-1-yl)phenyl)methanol (0.71 g)in THF (15.0 mL) was added thionyl chloride (0.40 mL) under ice-cooling,and the mixture was stirred at room temperature for 16 hr. The reactionmixture was diluted with ethyl acetate, saturated aqueous sodiumbicarbonate was added thereto, and the mixture was partitioned. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (0.50 g).

MS: [M+H]⁺ 211.1.

D) methyl5-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-2-hydroxy-3,4-dimethylbenzoate

To a mixture of methyl2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(0.51 g), 1-(4-(chloromethyl)-3-fluorophenyl)-1H-pyrazole (0.35 g) andsodium carbonate (0.35 g) in 1,2-dimethoxyethane (7.80 mL)-water (2.60mL) was added tetrakis(triphenylphosphine)palladium(0) (0.10 g), and themixture was stirred overnight at 80° C. under argon atmosphere. To thereaction mixture were added water and ethyl acetate, and the mixture waspartitioned. The organic layer was washed with water and saturatedbrine, and dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.54 g).

MS: [M+H]⁺ 355.2.

E) methyl5-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-3,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl5-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-2-hydroxy-3,4-dimethylbenzoate(0.54 g) in DMF (11.0 mL) were added sodium hydride (0.07 g) andN-phenylbis(trifluoromethanesulfonimide) (0.60 g) under ice-cooling, andthe mixture was stirred for 2 hr. To the reaction mixture was added 1Nhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium bicarbonatesolution and saturated brine, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.50 g).

MS: [M+H]⁺ 487.1.

F) methyl5-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-3,4-dimethyl-2-vinylbenzoate

To a solution of methyl5-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-3,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate(0.50 g) in DMF (10.0 mL) were added tributylvinyltin (0.50 g),trans-dichlorobis(triphenylphosphine)palladium(II) (0.04 g) and lithiumchloride (0.32 g), and the mixture was stirred at 90° C. for 1.5 hrunder argon atmosphere. To the reaction mixture was added aqueouspotassium fluoride solution, and the precipitated insoluble substancewas removed by filtration through Celite. The filtrate was diluted withethyl acetate, and the mixture was washed with water and saturatedbrine. The organic layer was dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.40 g).

MS: [M+H]⁺ 365.2.

G) methyl5-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-2-formyl-3,4-dimethylbenzoate

To a solution of methyl5-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-3,4-dimethyl-2-vinylbenzoate(0.40 g) in a mixed solvent of acetone (5.00 mL)-acetonitrile (5.00mL)-water (5.00 mL) were added osmium oxide (fixed catalyst I) (0.14 g)and sodium periodate (1.17 g), and the mixture was stirred overnight atroom temperature. The reaction mixture was filtered, and the filtratewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure to give the titlecompound (0.40 g) as a crude product. This compound was used in the nextstep without an additional purification.

H)6-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-2-((1S,2S)-2-hydroxycyclopentyl)-4,5-dimethylisoindolin-1-one

A solution of methyl5-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-2-formyl-3,4-dimethylbenzoate(0.17 g), (1S,2S)-2-aminocyclopentanol hydrochloride (0.06 g),triethylamine (0.06 mL) and anhydrous magnesium sulfate (0.10 g) in THF(3.40 mL) was stirred at room temperature for 10 hr. The insolublesubstance was removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was diluted with methanol (3.40 mL)and THF (3.40 mL), sodium triacetoxyborohydride (0.19 g) was addedthereto, and the mixture was stirred overnight at room temperature. Thereaction mixture was diluted with ethyl acetate, and the mixture waswashed with water and saturated brine. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.07g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.45-1.60 (1H, m), 1.62-1.79 (3H, m),1.80-1.98 (2H, m), 2.24 (3H, s), 2.25 (3H, s), 4.08-4.29 (4H, m), 4.39(2H, s), 4.88 (1H, d, J=4.9 Hz), 6.52-6.58 (1H, m), 7.15 (1H, t, J=8.4Hz), 7.23 (1H, s), 7.63 (1H, dd, J=8.3, 2.1 Hz), 7.68-7.77 (2H, m), 8.52(1H, d, J=2.5 Hz).

Example 171,5-anhydro-2-(6-(4-chlorobenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,4-dideoxy-L-threo-pentitolA) methyl 5-(4-chlorobenzyl)-2-hydroxy-3,4-dimethylbenzoate

To a solution of methyl2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(0.70 g) in DME (14.0 mL) were added 1-(bromomethyl)-4-chlorobenzene(0.49 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.09 g) and 2 mol/L aqueous sodium carbonatesolution (2.29 mL), and the mixture was stirred overnight at 80° C.under argon atmosphere. The reaction mixture was allowed to be cooled toroom temperature, water and ethyl acetate were added thereto, and themixture was partitioned. The organic layer was washed with water andsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.50 g).

MS: [M+H]⁺ 305.1.

B) methyl 5-(4-chlorobenzyl)-3,4-dimethyl-2-vinylbenzoate

To a solution of methyl5-(4-chlorobenzyl)-2-hydroxy-3,4-dimethylbenzoate (0.50 g) in DMF (10.0mL) was added sodium hydride (0.08 g) under ice-cooling, and the mixturewas stirred at room temperature for 30 min. To this reaction mixture wasadded N-phenylbis(trifluoromethanesulfonimide) (0.65 g) underice-cooling, and the mixture was stirred at room temperature for 1 hr.To the reaction mixture was added 1N hydrochloric acid, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedcrude methyl5-(4-chlorobenzyl)-3,4-dimethyl-2-{[(trifluoromethyl)sulfonyl]oxy}benzoatewas used in the next step without an additional purification.

The above-mentioned compound was dissolved in DMF (10.0 mL), to thesolution were added tributylvinyltin (0.72 mL),trans-dichlorobis(triphenylphosphine)palladium(II) (0.23 g) and lithiumchloride (0.52 g), and the mixture was stirred overnight at 90° C. underargon atmosphere. To the reaction mixture was added aqueous potassiumfluoride solution, and the precipitated insoluble substance was removedby filtration through Celite. The filtrate was diluted with ethylacetate, and the mixture was washed with water and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.17 g).

MS: [M+H]⁺ 315.2.

C) methyl 5-(4-chlorobenzyl)-2-formyl-3,4-dimethylbenzoate

To a solution of methyl 5-(4-chlorobenzyl)-3,4-dimethyl-2-vinylbenzoate(0.17 g) in a mixed solvent of acetone (4.00 mL)-acetonitrile (4.00mL)-water (4.00 mL) were added osmium oxide (fixed catalyst I) (0.07 g)and sodium periodate (0.58 g), and the mixture was stirred overnight atroom temperature under argon atmosphere. The reaction mixture wasfiltered, the filtrate was concentrated under reduced pressure, and theresidue was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.02 g).

MS: [M+H]⁺ 317.1.

D)1,5-anhydro-2-(6-(4-chlorobenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,4-dideoxy-L-threo-pentitol

To a solution of methyl 5-(4-chlorobenzyl)-2-formyl-3,4-dimethylbenzoate(0.02 g) in THF (1.00 mL) was added(3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (8.14 mg), and the mixture wasstirred at room temperature for 2 hr. The reaction mixture wasconcentrated, and the residue was diluted with methanol (1.00 mL).Sodium triacetoxyborohydride (0.02 g) was added thereto under argonatmosphere, and the mixture was stirred overnight at room temperature.The reaction mixture was diluted with ethyl acetate, and the mixture waswashed with water and saturated brine. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by reverse-phase HPLC. Thefractions were combined, saturated aqueous sodium hydrogencarbonatesolution was added thereto, and the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure to give the titlecompound (5.60 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.72-1.88 (1H, m), 2.09-2.17 (1H, m), 2.20(3H, s), 2.25 (3H, s), 3.45-3.62 (2H, m), 4.01-4.20 (6H, m), 4.26-4.50(2H, m), 7.02 (2H, d, J=8.5 Hz), 7.19-7.25 (2H, m), 7.51 (1H, s). 1Hundetected.

Example 18-12-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-6-(4-methoxybenzyl)-4,5-dimethyl-2,3-dihydro-1H-isoindol-1-oneAlias;1,5-anhydro-2,4-dideoxy-2-(6-(4-methoxybenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitolA) methyl 2-hydroxy-5-(4-methoxybenzyl)-3,4-dimethylbenzoate

To a mixture of methyl2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(18.3 g), 1-(chloromethyl)-4-methoxybenzene (9.38 g) and sodiumcarbonate (12.7 g) in 1,2-dimethoxyethane (255 mL)-water (85.0 mL) wasadded tetrakis(triphenylphosphine)palladium(0) (3.46 g), and the mixturewas stirred overnight at 80° C. under argon atmosphere. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated, washed with saturated brine. The organic layer was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. To the residue was added a mixed solvent of ethylacetate-diisopropyl ether, and the solid was collected by filtration togive the title compound (11.12 g). The filtrate was concentrated, andthe residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (4.99 g).

MS: [M+H]⁺ 301.1.

B) methyl5-(4-methoxybenzyl)-3,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl2-hydroxy-5-(4-methoxybenzyl)-3,4-dimethylbenzoate (16.1 g) in DMF (300mL) were added sodium hydride (2.57 g) andN-phenylbis(trifluoromethanesulfonimide) (21.1 g) under ice-cooling, andthe mixture was stirred at room temperature for 2.5 hr. To the reactionmixture was added 1N hydrochloric acid, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium bicarbonate solution and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (26.1g).

¹H NMR (300 MHz, CDCl₃) (2.22 (3H, s), 2.31 (3H, s), 3.79 (3H, s), 3.92(3H, s), 3.99 (2H, s), 6.83 (2H, d, J=8.7 Hz), 7.01 (2H, d, J=8.7 Hz),7.64 (1H, s).

C) methyl 5-(4-methoxybenzyl)-3,4-dimethyl-2-vinylbenzoate

To a solution of methyl5-(4-methoxybenzyl)-3,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate(23.2 g) in DMF (360 mL) were added tributylvinyltin (25.5 g),trans-dichlorobis(triphenylphosphine)palladium(II) (1.88 g) and lithiumchloride (16.8 g), and the mixture was stirred at 90° C. for 1.5 hrunder argon atmosphere. To the reaction mixture was added aqueouspotassium fluoride solution, and the precipitated insoluble substancewas removed by filtration through Celite. The filtrate was diluted withethyl acetate, and the mixture was washed with water and saturatedbrine. The organic layer was dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (13.6 g).

MS: [M+H]⁺ 311.2.

D) methyl 2-formyl-5-(4-methoxybenzyl)-3,4-dimethylbenzoate

To a solution of methyl 5-(4-methoxybenzyl)-3,4-dimethyl-2-vinylbenzoate(13.6 g) in a mixed solvent of acetone (135 mL)-acetonitrile (135mL)-water (135 mL) were added osmium oxide (fixed catalyst I) (5.57 g)and sodium periodate (46.9 g), and the mixture was stirred overnight atroom temperature. The reaction mixture was filtered, and the filtratewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure to give the titlecompound (13.5 g) as a crude product. This compound was used in the nextstep without an additional purification.

MS: [M+H]⁺ 313.2.

E)2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-6-(4-methoxybenzyl)-4,5-dimethyl-2,3-dihydro-1H-isoindol-1-oneAlias;1,5-anhydro-2,4-dideoxy-2-(6-(4-methoxybenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

To a solution of methyl2-formyl-5-(4-methoxybenzyl)-3,4-dimethylbenzoate (13.5 g) in THF (270mL) were added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (5.06 g) andanhydrous magnesium sulfate (9.99 g), and the mixture was stirred atroom temperature for 5 hr. The insoluble substance was removed byfiltration, and the filtrate was concentrated. The residue was dilutedwith methanol (220 mL)-THF (250 mL), sodium triacetoxyborohydride (18.3g) was added thereto, and the mixture was stirred at room temperaturefor 15 hr. The reaction mixture was diluted with ethyl acetate, themixture was washed with water and saturated brine, and the organic layerwas dried over anhydrous magnesium sulfate. The organic layer wasconcentrated under reduced pressure. The resulting solid was washed withethyl acetate to give the crude title compound (6.4 g). The filtrate wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.85 g). The crude title compound and the title compoundpurified by column were combined, and recrystallized from ethanol togive the title compound (6.48 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.44-1.65 (1H, m), 1.95 (1H, d, J=11.3 Hz),2.19 (3H, s), 2.21 (3H, s), 3.33-3.49 (2H, m), 3.71 (4H, s), 3.82-3.96(3H, m), 4.00 (2H, s), 4.33-4.50 (2H, m), 5.05 (1H, d, J=4.9 Hz), 6.84(2H, d, J=8.7 Hz), 7.03 (2H, d, J=8.7 Hz), 7.28 (1H, s).

X-ray powder diffraction pattern with specific peaks at d value (ord-spacing)=18.3, 9.8, 9.2, 6.8, 6.1, 5.2, 4.6, 4.2 and 3.8 Å.

Example 18-22-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-6-(4-methoxybenzyl)-4,5-dimethyl-2,3-dihydro-1H-isoindol-1-oneAlias;1,5-anhydro-2,4-dideoxy-2-(6-(4-methoxybenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

This compound was also synthesized by the following method.

A) methyl 2-hydroxy-5-(4-methoxybenzyl)-3,4-dimethylbenzoate

To a mixture of methyl2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(0.40 g), 1-(chloromethyl)-4-methoxybenzene (0.21 g) and sodiumcarbonate (0.28 g) in 1,2-dimethoxyethane (6.00 mL)-water (2.00 mL) wasadded tetrakis(triphenylphosphine)palladium(0) (0.08 g), and the mixturewas stirred overnight at 80° C. under argon atmosphere. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was separated, washed with saturated brine,and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.30 g).

¹H NMR (300 MHz, CDCl₃) δ 2.13 (3H, s), 2.19 (3H, s), 3.77 (3H, s), 3.90(2H, s), 3.91 (3H, s), 6.80 (2H, d, J=8.7 Hz), 6.99 (2H, d, J=8.7 Hz),7.50 (1H, s), 10.97 (1H, s).

B) methyl5-(4-methoxybenzyl)-3,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a mixture of methyl2-hydroxy-5-(4-methoxybenzyl)-3,4-dimethylbenzoate (0.30 g), sodiumhydride (0.05 g) and DMF (6.00 mL) was addedN-phenylbis(trifluoromethanesulfonimide) (0.39 g) under ice-cooling, andthe mixture was stirred at room temperature for 2 hr. To the reactionmixture was added 1N hydrochloric acid, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium bicarbonate solution and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.34g).

¹H NMR (300 MHz, CDCl₃) δ 2.21 (3H, s), 2.30 (3H, s), 3.78 (3H, s), 3.91(3H, s), 3.98 (2H, s), 6.78-6.87 (2H, m), 7.00 (2H, d, J=8.7 Hz), 7.63(1H, s).

C) methyl 5-(4-methoxybenzyl)-3,4-dimethyl-2-vinylbenzoate

To a solution of methyl5-(4-methoxybenzyl)-3,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate(0.34 g) in DMF (7.00 mL) were added tributylvinyltin (0.37 g),trans-dichlorobis(triphenylphosphine)palladium(II) (0.03 g) and lithiumchloride (0.25 g), and the mixture was stirred at 90° C. for 2 hr underargon atmosphere. To the reaction mixture was added aqueous potassiumfluoride solution, and the precipitated insoluble substance was removedby filtration through Celite. The filtrate was diluted with ethylacetate, and the mixture was washed with saturated brine. The organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.20 g).

¹H NMR (300 MHz, CDCl₃) δ 2.17 (3H, s), 2.26 (3H, s), 3.77 (3H, s), 3.80(3H, s), 3.97 (2H, s), 5.10 (1H, dd, J=17.7, 1.9 Hz), 5.43 (1H, dd,J=11.3, 1.9 Hz), 6.76-6.86 (2H, m), 6.96-7.09 (3H, m), 7.41 (1H, s).

D) methyl 2-formyl-5-(4-methoxybenzyl)-3,4-dimethylbenzoate

To a solution of methyl 5-(4-methoxybenzyl)-3,4-dimethyl-2-vinylbenzoate(0.19 g) in a mixed solvent of acetone (2.30 mL)-acetonitrile (2.30mL)-water (2.30 mL) were added osmium oxide (fixed catalyst I) (0.08 g)and sodium periodate (0.67 g), and the mixture was stirred overnight atroom temperature. The reaction mixture was filtered, and the filtratewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure to give the titlecompound (0.19 g) as a crude product. This compound was used in the nextstep without an additional purification.

MS: [M+H]⁺ 313.2.

E)2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-6-(4-methoxybenzyl)-4,5-dimethyl-2,3-dihydro-1H-isoindol-1-oneAlias;1,5-anhydro-2,4-dideoxy-2-(6-(4-methoxybenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

To a solution of methyl2-formyl-5-(4-methoxybenzyl)-3,4-dimethylbenzoate (0.10 g) in THF (1.90mL) were added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.04 g) andanhydrous magnesium sulfate (0.07 g), and the mixture was stirred atroom temperature for 5 hr. The insoluble substance was removed byfiltration, and the filtrate was concentrated. The residue was dilutedwith methanol (1.90 mL)-THF (1.90 mL), sodium triacetoxyborohydride(0.13 g) was added thereto, and the mixture was stirred at roomtemperature for 2.5 days. The reaction mixture was diluted with ethylacetate, and the mixture was washed with water and saturated brine. Theorganic layer was concentrated under reduced pressure, and the residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give the title compound (0.04 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.48-1.64 (1H, m), 1.94 (1H, d, J=14.7 Hz),2.19 (3H, s), 2.21 (3H, s), 3.35-3.44 (2H, m), 3.65-3.74 (4H, m),3.82-3.95 (3H, m), 4.00 (2H, s), 4.34-4.49 (2H, m), 5.04 (1H, d, J=5.3Hz), 6.84 (2H, d, J=8.7 Hz), 7.03 (2H, d, J=8.3 Hz), 7.28 (1H, s).

Example 191,5-anhydro-2,4-dideoxy-2-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitolA) 2-fluoro-N-methyl-4-vinylbenzamide

A mixture of 4-bromo-2-fluoro-N-methylbenzamide (0.80 g), vinylboronicacid pinacol cyclic ester (0.80 g) and 2M aqueous sodium carbonatesolution (3.45 mL) in DME (17.3 mL) was argon-purged.Bis(triphenylphosphine)palladium(II) dichloride (0.12 g) was addedthereto, and the mixture was stirred overnight at 80° C. The reactionsolution was diluted with ethyl acetate, and the mixture was washed withwater and saturated brine. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was subjected to short silica gel columnchromatography, and the solvent was evaporated under reduced pressure togive the title compound (0.74 g).

MS: [M+H]⁺ 180.1.

B) 2-fluoro-4-formyl-N-methylbenzamide

To a solution of 2-fluoro-N-methyl-4-vinylbenzamide (0.62 g) in a mixedsolvent of acetone (23 mL)-acetonitrile (23 mL)-water (23 mL) were addedosmium oxide (fixed catalyst I) (0.44 g) and sodium periodate (3.69 g),and the mixture was stirred overnight at room temperature. The insolublesubstance was removed by filtration, and the filtrate was diluted withethyl acetate and water. The insoluble substance was removed byfiltration, the filtrate was concentrated under reduced pressure, andthe residue was diluted with ethyl acetate. The mixture was washed withwater and saturated brine, the organic layer was dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was subjected to short silica gel columnchromatography, and the solvent was evaporated under reduced pressure togive the title compound (0.62 g).

MS: [M+H]⁺ 182.1.

C) 2-fluoro-4-(hydroxymethyl)-N-methylbenzamide

To a solution of 2-fluoro-4-formyl-N-methylbenzamide (0.62 g) inmethanol (17 mL) was added sodium borohydride (0.16 g) in smallportions, and the mixture was stirred at room temperature for 3 days. Tothe reaction mixture was added aqueous ammonium chloride, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.44 g).

MS: [M+H]⁺ 184.1.

D) 4-(chloromethyl)-2-fluoro-N-methylbenzamide

To a solution of 2-fluoro-4-(hydroxymethyl)-N-methylbenzamide (2.11 g)in THF (46.1 mL) was added dropwise thionyl chloride (1.01 mL) underice-cooling, and the mixture was stirred overnight at room temperature.To the reaction solution was added saturated aqueous sodium bicarbonate,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue wassubjected to silica gel column chromatography (ethyl acetate/hexane).The objective fractions were collected, and washed with diisopropylether, and the precipitate was collected by filtration. The filtrate wasconcentrated, and the residue was washed with diisopropyl ether. Thisprocedure was repeated three times to give the title compound (0.96 g).

MS: [M+H]⁺ 202.1.

E) methyl5-(3-fluoro-4-(methylcarbamoyl)benzyl)-2-hydroxy-3,4-dimethylbenzoate

To a mixture of methyl2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(0.35 g), 4-(chloromethyl)-2-fluoro-N-methylbenzamide (0.23 g) andsodium carbonate (0.24 g) in 1,2-dimethoxyethane (5.40 mL)-water (1.80mL) was added tetrakis(triphenylphosphine)palladium(0) (0.07 g), and themixture was stirred overnight at 80° C. under argon atmosphere. To thereaction mixture were added water and ethyl acetate, and the mixture waspartitioned. The organic layer was washed with water and saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.37 g).

MS: [M+H]⁺ 346.2.

F) methyl5-(3-fluoro-4-(methylcarbamoyl)benzyl)-3,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl5-(3-fluoro-4-(methylcarbamoyl)benzyl)-2-hydroxy-3,4-dimethylbenzoate(0.36 g) in DMF (7.00 mL) were added sodium hydride (0.05 g) andN-phenylbis(trifluoromethanesulfonimide) (0.41 g) under ice-cooling, andthe mixture was stirred for 2 hr. To the reaction mixture was added 1Nhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium bicarbonatesolution and saturated brine, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.29 g).

MS: [M+H]⁺ 478.0.

G) methyl5-(3-fluoro-4-(methylcarbamoyl)benzyl)-3,4-dimethyl-2-vinylbenzoate

To a solution of methyl5-(3-fluoro-4-(methylcarbamoyl)benzyl)-3,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate(0.28 g) in DMF (6.00 mL) were added tributylvinyltin (0.29 g),trans-dichlorobis(triphenylphosphine)palladium(II) (0.02 g) and lithiumchloride (0.19 g), and the mixture was stirred at 90° C. for 2 hr underargon atmosphere. To the reaction mixture was added aqueous potassiumfluoride solution, and the precipitated insoluble substance was removedby filtration through Celite. The filtrate was diluted with ethylacetate, and the mixture was washed with water and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.19 g).

MS: [M+H]⁺ 356.1.

H) methyl5-(3-fluoro-4-(methylcarbamoyl)benzyl)-2-formyl-3,4-dimethylbenzoate

To a solution of methyl5-(3-fluoro-4-(methylcarbamoyl)benzyl)-3,4-dimethyl-2-vinylbenzoate(0.19 g) in a mixed solvent of acetone (2.20 mL)-acetonitrile (2.20mL)-water (2.20 mL) were added osmium oxide (fixed catalyst I) (0.07 g)and sodium periodate (0.56 g), and the mixture was stirred overnight atroom temperature. The reaction mixture was filtered, and the filtratewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure to give the titlecompound (0.19 g) as a crude product. This compound was used in the nextstep without an additional purification.

MS: [M+H]⁺ 358.2.

I)1,5-anhydro-2,4-dideoxy-2-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

To a solution of methyl5-(3-fluoro-4-(methylcarbamoyl)benzyl)-2-formyl-3,4-dimethylbenzoate(0.09 g) in THF (2.00 mL) were added(3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.03 g) and anhydrous magnesiumsulfate (0.06 g), and the mixture was stirred at room temperature for 5hr. The reaction mixture was concentrated, and the residue was dilutedwith methanol (2.00 mL)-THF (2.00 mL). Sodium triacetoxyborohydride(0.11 g) was added thereto, and the mixture was stirred overnight atroom temperature. The reaction mixture was diluted with ethyl acetate,and the mixture was washed with water and saturated brine. The organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (methanol/ethyl acetate) to give the titlecompound (0.04 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.47-1.63 (1H, m), 1.89-1.99 (1H, m), 2.18(3H, s), 2.22 (3H, s), 2.75 (3H, d, J=4.5 Hz), 3.40 (2H, d, J=10.5 Hz),3.70 (1H, dd, J=10.9, 3.4 Hz), 3.81-3.97 (3H, m), 4.14 (2H, s),4.35-4.51 (2H, m), 5.05 (1H, d, J=5.3 Hz), 6.96-7.05 (2H, m), 7.36 (1H,s), 7.54 (1H, t, J=7.9 Hz), 8.14 (1H, brs).

Example 20-14-fluoro-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-TH-isoindol-1-oneAlias;1,5-anhydro-2,4-dideoxy-2-(4-fluoro-5-methyl-1-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitolA) 3-fluoro-2-hydroxy-4-methylbenzoic acid

To an aqueous solution (50.0 mL) of sodium chlorite (22.2 g) was added amixture of 3-fluoro-2-hydroxy-4-methylbenzaldehyde (9.47 g), sodiumdihydrogenphosphate (33.2 g) and 2-methyl-2-butene (32.5 mL) intert-butanol (200 mL)-water (100 mL) under ice-cooling, and the mixturewas stirred at the same temperature for 3 hr. The pH of the reactionmixture was adjusted to 2-3 with 2N hydrochloric acid. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure to give the title compound (10.5 g) asa crude product. This compound was used in the next step without anadditional purification.

B) methyl 3-fluoro-2-hydroxy-4-methylbenzoate

To a solution of 3-fluoro-2-hydroxy-4-methylbenzoic acid (10.5 g) inmethanol (50.0 mL) was added sulfuric acid (5.00 mL) at roomtemperature, and the mixture was stirred at 60° C. for 24 hr. Thesolvent was evaporated under reduced pressure, to the residue were addedwater and ethyl acetate, and the mixture was extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (6.40 g).

MS: [M+H]⁺ 185.0.

C) methyl 5-bromo-3-fluoro-2-hydroxy-4-methylbenzoate

To a solution of methyl 3-fluoro-2-hydroxy-4-methylbenzoate (6.40 g) inacetic acid (120 mL) was added bromine (1.87 mL) at room temperature,and the mixture was stirred at the same temperature for 2 hr. To thereaction mixture was added 10% aqueous sodium thiosulfate solution, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reduced pressureto give a mixture (7.99 g) of the title compound and the raw material(about 2:1). The obtained product was used in the next step without anadditional purification.

¹H NMR (300 MHz, CDCl₃) δ 2.38 (3H, d, J=2.8 Hz), 3.98 (3H, s), 7.82(1H, d, J=2.1 Hz), 10.67 (1H, s).

D) methyl3-fluoro-2-hydroxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

trans-Dichlorobis(triphenylphosphine)palladium(II) (1.07 g) was added toa mixture of the 2:1 mixture (7.99 g) of methyl5-bromo-3-fluoro-2-hydroxy-4-methylbenzoate and methyl3-fluoro-2-hydroxy-4-methylbenzoate, bis(pinacolato)diboron (11.6 g),potassium acetate (8.94 g) and toluene (160 mL) at room temperatureunder argon atmosphere, and the mixture was stirred at 100° C. for 2 hr.To the reaction mixture was again addedtrans-dichlorobis(triphenylphosphine)palladium(II) (1.07 g), and themixture was stirred at 100° C. for 3 days. To the reaction mixture wasagain added trans-dichlorobis(triphenylphosphine)palladium(II) (1.07 g),and the mixture was stirred overnight at 100° C. The reaction mixturewas allowed to be cooled to room temperature, water was added thereto,and the precipitate was removed by filtration. The filtrate wasextracted with ethyl acetate, the organic layer was washed with waterand saturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (2.20 g). In addition, the title compound (4.03 g) wasobtained from second fraction of column chromatography.

MS: [M+H]⁺ 311.1.

E) methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-2-hydroxy-4-methylbenzoate

Tetrakis(triphenylphosphine)palladium(0) (0.40 g) was added to a mixtureof methyl3-fluoro-2-hydroxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(2.13 g), 1-(4-(chloromethyl)phenyl)-1H-pyrazole (1.32 g), sodiumcarbonate (1.46 g), DME (30.0 mL) and water (10.0 mL) under argonatmosphere, and the mixture was stirred overnight at 80° C. The reactionmixture was allowed to be cooled to room temperature, water was addedthereto, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (0.33 g).

MS: [M+H]⁺ 341.1.

F) methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-4-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-2-hydroxy-4-methylbenzoate (0.33g) in DMF (7.0 mL) were added sodium hydride (0.047 g) andN-phenylbis(trifluoromethanesulfonimide) (0.38 g) under ice-cooling, andthe mixture was stirred at room temperature for 2 hr. To the reactionmixture was added 1N hydrochloric acid, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium bicarbonate solution and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.36g).

MS: [M+H]⁺ 473.1.

G) methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-4-methyl-2-vinylbenzoate

A mixture of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-4-methyl-2-((trifluoromethyl)sulfonyl)oxy)benzoate(0.36 g), tributylvinyltin (0.33 mL),trans-dichlorobis(triphenylphosphine)palladium(II) (0.03 g), lithiumchloride (0.24 g) and DMF (7.2 mL) was stirred at 90° C. for 1 hr underargon atmosphere. To the reaction mixture was added aqueous potassiumfluoride solution, and the insoluble substance was removed by filtrationthrough Celite. The filtrate was diluted with ethyl acetate, and themixture was washed with saturated brine. The organic layer was driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.21g).

MS: [M+H]⁺ 351.2.

H) methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-2-formyl-4-methylbenzoate

To a mixture of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-4-methyl-2-vinylbenzoate (0.21g), acetone (2.3 mL), acetonitrile (2.3 mL) and water (2.3 mL) wereadded osmium oxide (fixed catalyst I) (0.08 g) and sodium periodate(0.63 g) at room temperature, and the mixture was stirred overnight atthe same temperature. The insoluble substance was removed by filtration,and the filtrate was diluted with ethyl acetate. The solution was washedwith saturated brine, and dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure to give the titlecompound (0.21 g) as a crude product. This compound was used in the nextstep without an additional purification.

MS: [M+H]⁺ 353.1.

I)4-fluoro-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindol-1-oneAlias;1,5-anhydro-2,4-dideoxy-2-(4-fluoro-5-methyl-1-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

A mixture of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-2-formyl-4-methylbenzoate (0.21g), (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.07 g), anhydrousmagnesium sulfate (0.14 g) and THF (4.00 mL) was stirred at roomtemperature for 6 hr under nitrogen atmosphere. The insoluble substancewas removed by filtration, and the filtrate was concentrated. Theresidue was dissolved in a mixed solvent of methanol (4.00 mL)-THF (4.00mL), sodium triacetoxyborohydride (0.25 g) was added thereto, and themixture was stirred at room temperature for 16 hr. The reaction mixturewas diluted with ethyl acetate, and the mixture was washed with waterand saturated brine. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (0.11 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.45-1.64 (1H, m), 1.88-1.99 (1H, m), 2.23(3H, d, J=2.1 Hz), 3.33-3.47 (2H, m), 3.64-3.95 (4H, m), 4.15 (2H, s),4.55 (2H, s), 5.08 (1H, d, J=5.1 Hz), 6.49-6.56 (1H, m), 7.27 (2H, d,J=8.7 Hz), 7.38 (1H, s), 7.68-7.81 (3H, m), 8.44 (1H, d, J=2.1 Hz).

Example 20-24-fluoro-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindol-1-oneAlias;1,5-anhydro-2,4-dideoxy-2-(4-fluoro-5-methyl-1-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

This compound was also synthesized by the following method.

A) 3-fluoro-2-hydroxy-4-methylbenzoic acid

A mixture of 2,3-difluoro-4-methylbenzoic acid (25.0 g), sodiumhydroxide (23.2 g) and DMSO (250 mL) was stirred at 140° C. for 12 hr,and then overnight at room temperature, under argon atmosphere. To thereaction mixture was added 6M hydrochloric acid (100 mL) underice-cooling. Ethyl acetate and water were added thereto at roomtemperature, the organic layer was separated, and the aqueous layer wasextracted with ethyl acetate. The organic layers were combined, washedwith water and saturated brine, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure to givethe title compound (24.3 g). This compound was used in the next stepwithout an additional purification.

¹H NMR (300 MHz, CDCl₃) δ 2.35 (3H, d, J=2.3 Hz), 6.74 (1H, dd, J=7.9,6.8 Hz), 7.58 (1H, dd, J=8.3, 1.5 Hz), 10.37 (1H, s), 1H undetected.

B) methyl 3-fluoro-2-hydroxy-4-methylbenzoate

To a solution of 3-fluoro-2-hydroxy-4-methylbenzoic acid (24.3 g) inmethanol (500 mL) was added sulfuric acid (7.60 mL) at room temperature,and the mixture was stirred at 60° C. for 3 days. The solvent wasevaporated under reduced pressure, and ethyl acetate and saturated brinewere added thereto. The organic layer was separated, and the aqueouslayer was extracted with ethyl acetate. The combined organic layers werewashed with water and saturated brine, and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. To the residue was added diisopropyl ether (50 mL), and theinsoluble substance was removed by filtration. The filtrate wasconcentrated under reduced pressure to give the title compound (25.4 g).

¹H NMR (300 MHz, CDCl₃) δ 2.32 (3H, d, J=2.5 Hz), 3.95 (3H, s), 6.68(1H, dd, J=7.9, 6.8 Hz), 7.49 (1H, dd, J=8.3, 1.7 Hz), 10.74 (1H, s).

C) methyl 5-bromo-3-fluoro-2-hydroxy-4-methylbenzoate

To a solution of methyl 3-fluoro-2-hydroxy-4-methylbenzoate (25.4 g) inacetic acid (250 mL) was added bromine (7.78 mL), and the mixture wasstirred at room temperature for 3 hr. To the reaction mixture was added5% aqueous sodium thiosulfate solution (250 mL) at room temperature, andthe precipitate was collected by filtration, and washed with water togive the title compound (21.1 g).

¹H NMR (300 MHz, CDCl₃) δ 2.37 (3H, d, J=2.6 Hz), 3.97 (3H, s), 7.81(1H, d, J=1.7 Hz), 10.65 (1H, s).

D) methyl3-fluoro-2-hydroxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

trans-Dichlorobis(triphenylphosphine)palladium(II) (2.0 g) was added toa mixture of methyl 5-bromo-3-fluoro-2-hydroxy-4-methylbenzoate (15.0g), bis(pinacolato)diboron (21.7 g), potassium acetate (16.8 g) andtoluene (290 mL) under argon atmosphere, and the mixture was stirred at110° C. for 15 hr. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was washed with diisopropyl ether to give the title compound(12.3 g). The filtrate was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (1.99 g).

MS: [M+H]⁺ 311.2.

E) methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-2-hydroxy-4-methylbenzoate

Tetrakis(triphenylphosphine)palladium(0) (2.52 g) was added to a mixtureof methyl3-fluoro-2-hydroxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(13.5 g), 1-(4-(chloromethyl)phenyl)-1H-pyrazole (8.39 g), sodiumcarbonate (9.23 g), DME (195 mL) and water (65.0 mL) under argonatmosphere, and the mixture was stirred overnight at 80° C. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was washed with a mixed solvent ofdiisopropyl ether-ethyl acetate to give a crude product. The filtratewas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/methanol). The obtainedcrude products are combined, and washed with diisopropyl ether-ethylacetate to give the title compound (12.4 g).

MS: [M+H]⁺ 341.1.

F) methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-4-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-2-hydroxy-4-methylbenzoate (12.4g) in DMF (250 mL) were added sodium hydride (1.74 g) andN-phenylbis(trifluoromethanesulfonimide) (14.3 g) under ice-cooling, andthe mixture was stirred at room temperature for 2 hr. To the reactionmixture was added 1N hydrochloric acid, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium bicarbonate solution and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (12.5g).

MS: [M+H]⁺ 473.1.

G) methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-4-methyl-2-vinylbenzoate

A mixture of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-4-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate(11.8 g), tributylvinyltin (11.9 g),trans-dichlorobis(triphenylphosphine)palladium(II) (0.88 g), lithiumchloride (7.84 g) and DMF (240 mL) was stirred at 90° C. for 1.5 hrunder argon atmosphere. To the reaction mixture was added aqueouspotassium fluoride solution, and the precipitated insoluble substancewas removed by filtration through Celite. The filtrate was diluted withethyl acetate, and the mixture was washed with saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (7.98 g).

MS: [M+H]⁺ 351.2.

H) methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-2-formyl-4-methylbenzoate

To a mixture of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-4-methyl-2-vinylbenzoate (7.97g), acetone (93.0 mL), acetonitrile (93.0 mL) and water (93.0 mL) wereadded osmium oxide (fixed catalyst I) (2.89 g) and sodium periodate(24.3 g) at room temperature, and the mixture was stirred overnight atthe same temperature. The insoluble substance was removed by filtration,and the filtrate was diluted with ethyl acetate. The solution was washedwith saturated brine, the organic layer was and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reduced pressureto give the title compound (7.97 g) as a crude product. This compoundwas used in the next step without an additional purification.

MS: [M+H]⁺ 353.2.

I)4-fluoro-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindol-1-oneAlias;1,5-anhydro-2,4-dideoxy-2-(4-fluoro-5-methyl-1-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

A mixture of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-2-formyl-4-methylbenzoate (7.97g), (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (2.65 g), anhydrousmagnesium sulfate (5.23 g) and THF (160 mL) was stirred at roomtemperature for 5 hr under nitrogen atmosphere. The insoluble substancewas removed by filtration, and the filtrate was concentrated. Theresidue was dissolved in a mixed solvent of methanol (120 mL)-THF (150mL), sodium triacetoxyborohydride (9.59 g) was added thereto, and themixture was stirred at room temperature for 15 hr. Sodiumtriacetoxyborohydride (9.59 g) was again added thereto, and the mixturewas stirred for 3 hr. The reaction mixture was diluted with ethylacetate, and the mixture was washed with water and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was dissolvedin DMSO-toluene, and the solution was purified by NH silica gel columnchromatography (ethyl acetate/hexane). The obtained crude product wasdissolved in THF, the solution was washed with water and saturatedbrine, and the solvent was evaporated under reduced pressure. Theresidue was washed with a mixed solvent of diisopropyl ether-ethylacetate to give a crude product. The crude product (5.28 g) wasdissolved in hot ethanol (60 mL), and recrystallized over 4 hr underice-cooling to give the title compound (4.88 g).

¹H NMR (300 MHz, CDCl₃) δ 1.71-1.87 (1H, m), 2.08-2.17 (1H, m), 2.22(3H, d, J=2.3 Hz), 2.47-2.57 (1H, m), 3.42-3.62 (2H, m), 3.97-4.15 (6H,m), 4.31-4.63 (2H; m), 6.39-6.50 (1H, m), 7.17 (2H, d, J=8.7 Hz), 7.47(1H, s), 7.59 (2H, d, J=8.7 Hz), 7.70 (1H, d, J=1.5 Hz), 7.88 (1H, d,J=2.3 Hz).

X-ray powder diffraction pattern with specific peaks at d value (ord-spacing)=12.8, 8.0, 7.5, 6.2, 6.0, 5.6, 5.0, 4.6, 4.5 and 4.2 Å.

Example 211,5-anhydro-2,4-dideoxy-2-(5-methyl-1-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

To a solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methylbenzoate (0.20 g) in THF(4.00 mL) was added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.07 g),and the mixture was stirred at room temperature for 4 hr under argonatmosphere. The reaction mixture was concentrated, and the residue wasdiluted with acetic acid (4.00 mL). Sodium triacetoxyborohydride (0.19g) was added thereto, and the mixture was stirred overnight at roomtemperature. The reaction mixture was diluted with saturated aqueoussodium bicarbonate solution and extracted with ethyl acetate, theorganic layer was washed with water and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.11g).

¹H NMR (300 MHz, CDCl₃) δ 1.71-1.90 (1H, m), 2.07-2.18 (1H, m), 2.31(3H, s), 2.69 (1H, d, J=5.5 Hz), 3.43-3.59 (2H, m), 3.98-4.15 (6H, m),4.29-4.55 (2H, m), 6.45 (1H, t, J=2.1 Hz), 7.18 (2H, d, J=8.5 Hz), 7.24(1H, s), 7.55-7.61 (2H, m), 7.63 (1H, s), 7.70 (1H, d, J=1.7 Hz), 7.88(1H, d, J=2.5 Hz).

Example 221,5-anhydro-2,4-dideoxy-2-(6-(4-(difluoromethoxy)benzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitolA) methyl 5-(4-(difluoromethoxy)benzyl)-2-hydroxy-3,4-dimethylbenzoate

To a solution of methyl2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(0.60 g) in DME (12.0 mL) were added1-(bromomethyl)-4-(difluoromethoxy)benzene (0.47 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.16 g) and 2 mol/L aqueous sodium carbonatesolution (1.96 mL), and the mixture was stirred overnight at 80° C.under argon atmosphere. Water and ethyl acetate were added thereto, themixture was allowed to be cooled to room temperature, and theprecipitate was removed by filtration. The filtrate was extracted withethyl acetate, the organic layer was washed with water and saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.60 g).

MS: [M+H]⁺ 337.0.

B) methyl 5-(4-(difluoromethoxy)benzyl)-3,4-dimethyl-2-vinylbenzoate

To a solution of methyl5-(4-(difluoromethoxy)benzyl)-2-hydroxy-3,4-dimethylbenzoate (0.60 g) inDMF (12.0 mL) was added sodium hydride (0.08 g) under ice-cooling, andthe mixture was stirred at room temperature for 30 min. To this reactionmixture was added N-phenylbis(trifluoromethanesulfonimide) (0.77 g)under ice-cooling, and the mixture was stirred at room temperature for 1hr. To the reaction mixture was added 1N hydrochloric acid underice-cooling, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained crude methyl5-[4-(difluoromethoxy)benzyl]-3,4-dimethyl-2-{[(trifluoromethyl)sulfonyl]oxy}benzoatewas used in the next step without an additional purification.

The above-mentioned compound was dissolved in DMF (12.0 mL),tributylvinyltin (0.78 mL),trans-dichlorobis(triphenylphosphine)palladium(II) (0.13 g) and lithiumchloride (0.53 g) were added thereto, and the mixture was stirredovernight at 90° C. under argon atmosphere. To the reaction mixture wasadded aqueous potassium fluoride solution, and the precipitatedinsoluble substance was removed by filtration through Celite. Thefiltrate was diluted with ethyl acetate, and the mixture was washed withwater and saturated brine. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (0.16 g).

MS: [M+H]⁺ 347.2.

C) methyl 5-(4-(difluoromethoxy)benzyl)-2-formyl-3,4-dimethylbenzoate

To a solution of methyl5-(4-(difluoromethoxy)benzyl)-3,4-dimethyl-2-vinylbenzoate (0.16 g) in amixed solvent of acetone (3.00 mL)-acetonitrile (3.00 mL)-water (3.00mL) were added osmium oxide (fixed catalyst I) (0.06 g) and sodiumperiodate (0.49 g), and the mixture was stirred overnight at roomtemperature. The reaction mixture was filtered, and the filtrate wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.04 g).

MS: [M+H]⁺ 349.1.

D)1,5-anhydro-2,4-dideoxy-2-(6-(4-(difluoromethoxy)benzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

To a solution of methyl5-(4-(difluoromethoxy)benzyl)-2-formyl-3,4-dimethylbenzoate (0.04 g) inTHF (2.00 mL) was added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.01 g)under argon atmosphere, and the mixture was stirred at room temperaturefor 3 hr. The reaction mixture was concentrated, and the residue wasdiluted with acetic acid (2.00 mL). Sodium triacetoxyborohydride (0.03g) was added thereto under argon atmosphere, and the mixture was stirredovernight at room temperature. The reaction mixture was diluted withsaturated aqueous sodium bicarbonate solution, and extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by NH silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.02 g).

¹H NMR (300 MHz, CDCl₃) δ 1.73-1.88 (1H, m), 2.09-2.18 (1H, m), 2.21(3H, s), 2.25 (3H, s), 2.52 (1H, d, J=5.3 Hz), 3.45-3.63 (2H, m),4.00-4.18 (6H, m), 4.26-4.50 (2H, m), 6.19-6.75 (1H, m), 6.99-7.04 (2H,m), 7.06-7.11 (2H, m), 7.51 (1H, s).

Example 231,5-anhydro-2,4-dideoxy-2-(6-(4-fluoro-3-methoxybenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitolA) methyl 5-(4-fluoro-3-methoxybenzyl)-2-hydroxy-3,4-dimethylbenzoate

To a solution of methyl2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(0.50 g) in DME (12.0 mL) were added4-(bromomethyl)-1-fluoro-2-methoxybenzene (0.39 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.07 g) and 2 mol/L aqueous sodium carbonatesolution (1.63 mL), and the mixture was stirred overnight at 80° C.under argon atmosphere. The reaction mixture was allowed to be cooled toroom temperature, and diluted with ethyl acetate, and the mixture waswashed with saturated brine. The organic layer was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.45 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.13 (6H, s), 3.78 (3H, s), 3.88 (3H, s),3.94 (2H, s), 6.53 (1H, ddd, J=8.3, 4.4, 2.1 Hz), 6.97 (1H, dd, J=8.5,1.9 Hz), 7.07 (1H, dd, J=11.5, 8.3 Hz), 7.49 (1H, s), 10.90 (1H, s).

B) methyl5-(4-fluoro-3-methoxybenzyl)-3,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl5-(4-fluoro-3-methoxybenzyl)-2-hydroxy-3,4-dimethylbenzoate (0.45 g) inDMF (5.0 mL) were added sodium hydride (0.07 g) andN-phenylbis(trifluoromethanesulfonimide) (0.55 g) under ice-cooling, andthe mixture was stirred at room temperature for 2 hr under argonatmosphere. The reaction mixture was diluted with ethyl acetate, and themixture was washed with saturated brine. The organic layer was driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.63g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.19-2.32 (6H, m), 3.76-3.85 (6H, m), 4.08(2H, s), 6.59 (1H, ddd, J=8.3, 4.3, 2.1 Hz), 6.99-7.16 (2H, m), 7.61(1H, s).

C) methyl 5-(4-fluoro-3-methoxybenzyl)-3,4-dimethyl-2-vinylbenzoate

To a solution of methyl5-(4-fluoro-3-methoxybenzyl)-3,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate(0.63 g) in DMF (7.00 mL) were added tributylvinyltin (0.61 mL),trans-dichlorobis(triphenylphosphine)palladium(II) (0.05 g) and lithiumchloride (0.44 g), and the mixture was stirred at 90° C. for 2 hr underargon atmosphere. To the reaction mixture was added aqueous potassiumfluoride solution, and the precipitated insoluble substance was removedby filtration through Celite. The filtrate was diluted with ethylacetate, and the mixture was washed with saturated brine. The organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.39 g).

MS: [M+H]⁺ 329.1.

D) methyl 5-(4-fluoro-3-methoxybenzyl)-2-formyl-3,4-dimethylbenzoate

To a solution of methyl5-(4-fluoro-3-methoxybenzyl)-3,4-dimethyl-2-vinylbenzoate (0.39 g) in amixed solvent of acetone (9.00 mL)-acetonitrile (9.00 mL)-water (9.00mL) were added osmium oxide (fixed catalyst I) (0.15 g) and sodiumperiodate (1.27 g), and the mixture was stirred at room temperature for2.5 days. The reaction mixture was filtered, and the filtrate wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate to give thetitle compound (0.39 g). This compound was used in the next step withoutan additional purification.

MS: [M+H]⁺ 331.1.

E)1,5-anhydro-2,4-dideoxy-2-(6-(4-fluoro-3-methoxybenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

To a solution of methyl5-(4-fluoro-3-methoxybenzyl)-2-formyl-3,4-dimethylbenzoate (0.35 g) inTHF (4.00 mL) were added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.12g) and anhydrous magnesium sulfate (0.26 g), and the mixture was stirredat room temperature for 5 hr under nitrogen atmosphere. The insolublesubstance was removed by filtration, the filtrate was concentrated, andthe residue was diluted with methanol (2.00 mL)-THF (4.00 mL). Sodiumtriacetoxyborohydride (0.45 g) was added thereto, and the mixture wasstirred overnight at room temperature. The reaction mixture was dilutedwith ethyl acetate, and the mixture was washed with water and saturatedbrine. The organic layer was dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.13 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.47-1.66 (1H, m), 1.89-2.00 (1H, m),2.18-2.26 (6H, m), 3.34-3.45 (2H, m), 3.69 (1H, dd, J=10.9, 3.4 Hz),3.78 (3H, s), 3.82-3.96 (3H, m), 4.05 (2H, s), 4.34-4.50 (2H, m), 5.05(1H, d, J=4.5 Hz), 6.49-6.61 (1H, m), 6.97-7.13 (2H, m), 7.30 (1H, s).

Example 241,5-anhydro-2-(4-chloro-6-(4-methoxybenzyl)-5-methyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,4-dideoxy-L-threo-pentitolA) methyl 5-bromo-3-chloro-2-hydroxy-4-methylbenzoate

To a solution of methyl 5-bromo-2-hydroxy-4-methylbenzoate (4.54 g) inDMF (34.0 mL) was added N-chlorosuccinimide (2.47 g), and the mixturewas stirred overnight at room temperature. To the reaction mixture wasadded water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure to give the title compound (5.20 g).

MS: [M−H]⁺ 276.7.

B) methyl3-chloro-2-hydroxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

To a solution of methyl 5-bromo-3-chloro-2-hydroxy-4-methylbenzoate(5.20 g) in toluene (140 mL) were added bis(pinacolato)diboron (7.09 g),potassium acetate (5.48 g) andtrans-dichlorobis(triphenylphosphine)palladium(II) (0.65 g), and themixture was stirred at 110° C. for 15 hr under argon atmosphere. Thereaction mixture was allowed to be cooled to room temperature, water andethyl acetate were added thereto, and the mixture was partitioned. Theorganic layer was washed with water and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (3.54g).

MS: [M+H]⁺ 327.1.

C) methyl 3-chloro-2-hydroxy-5-(4-methoxybenzyl)-4-methylbenzoate

To a solution of methyl3-chloro-2-hydroxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(0.90 g), in a mixed solvent of DME (13.5 mL)-water (4.50 mL) were added1-(chloromethyl)-4-methoxybenzene (0.43 g),tetrakis(triphenylphosphine)palladium(0) (0.16 g) and sodium carbonate(0.58 g), and the mixture was stirred at 80° C. overnight under argonatmosphere. The reaction mixture was allowed to be cooled to roomtemperature, water and ethyl acetate were added thereto, and the mixturewas partitioned. The organic layer was washed with water and saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.37 g).

MS: [M−H]⁺ 318.9.

D) methyl3-chloro-5-(4-methoxybenzyl)-4-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl3-chloro-2-hydroxy-5-(4-methoxybenzyl)-4-methylbenzoate (0.36 g) in DMF(7.50 mL) were added sodium hydride (0.05 g) andN-phenylbis(trifluoromethanesulfonimide) (0.36 g) under ice-cooling, andthe mixture was stirred at room temperature for 2.5 hr. To the reactionmixture was added 1N hydrochloric acid, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium bicarbonate solution and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.51g).

MS: [M−H]⁺ 451.8.

E) methyl 3-chloro-5-(4-methoxybenzyl)-4-methyl-2-vinylbenzoate

To a solution of methyl3-chloro-5-(4-methoxybenzyl)-4-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate(0.51 g) in DMF (10.0 mL) were added tributylvinyltin (0.54 g),trans-dichlorobis(triphenylphosphine)palladium(II) (0.04 g) and lithiumchloride (0.36 g), and the mixture was stirred at 90° C. for 1 hr underargon atmosphere. To the reaction mixture was added aqueous potassiumfluoride solution, and the precipitated insoluble substance was removedby filtration through Celite. The filtrate was diluted with ethylacetate, and the mixture was washed with water and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.31 g).

MS: [M+H]⁺ 331.1.

F) methyl 3-chloro-2-formyl-5-(4-methoxybenzyl)-4-methylbenzoate

To a solution of methyl3-chloro-5-(4-methoxybenzyl)-4-methyl-2-vinylbenzoate (0.31 g) in amixed solvent of acetone (3.60 mL)-acetonitrile (3.60 mL)-water (3.60mL) were added osmium oxide (fixed catalyst I) (0.12 g) and sodiumperiodate (1.00 g), and the mixture was stirred overnight at roomtemperature. The reaction mixture was filtered, and the filtrate wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure to give the title compound(0.31 g) as a crude product. This compound was used in the next stepwithout an additional purification.

G)1,5-anhydro-2-(4-chloro-6-(4-methoxybenzyl)-5-methyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,4-dideoxy-L-threo-pentitol

To a solution of methyl3-chloro-2-formyl-5-(4-methoxybenzyl)-4-methylbenzoate (0.10 g) in THF(2.00 mL) were added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.04 g)and anhydrous magnesium sulfate (0.07 g), and the mixture was stirred atroom temperature for 6 hr. The insoluble substance was removed byfiltration, the filtrate was concentrated, and the residue was dilutedwith methanol (2.00 mL)-THF (2.00 mL). Sodium triacetoxyborohydride(0.19 g) was added thereto, and the mixture was stirred overnight atroom temperature. The reaction mixture was diluted with ethyl acetate,and the mixture was washed with water and saturated brine. The organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.05 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.47-1.62 (1H, m), 1.89-1.99 (1H, m), 2.35(3H, s), 3.34-3.48 (2H, m), 3.64-3.74 (4H, m), 3.80-3.97 (3H, m), 4.07(2H, s), 4.39-4.54 (2H, m), 5.11 (1H, d, J=5.3 Hz), 6.82-6.90 (2H, m),7.05 (2H, d, J=8.7 Hz), 7.42 (1H, s).

Example 25-12-((1S,2S)-2-hydroxycyclohexyl)-4,5-dimethyl-6-((6-methylpyridin-3-yl)methyl)isoindolin-1-oneA) 5-(chloromethyl)-2-methylpyridine

To a solution of (6-methylpyridin-3-yl)methanol (1.08 g) in THF (15.0mL) was added thionyl chloride (1.57 g) under ice-cooling, and themixture was stirred overnight at room temperature. The reaction mixturewas diluted with water and ethyl acetate, saturated aqueous sodiumbicarbonate was added thereto, and the mixture was partitioned. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (0.81 g).

¹H NMR (300 MHz, CDCl₃) δ 2.57 (3H, s), 4.57 (2H, s), 7.17 (1H, d, J=7.9Hz), 7.63 (1H, dd, J=7.9, 2.3 Hz), 8.50 (1H, d, J=2.3 Hz).

B) methyl2-hydroxy-3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)benzoate

To a solution of methyl2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(0.80 g) in a mixed solvent of DME (12.0 mL)-water (4.00 mL) were added5-(chloromethyl)-2-methylpyridine (0.41 g),tetrakis(triphenylphosphine)palladium(0) (0.15 g) and sodium carbonate(0.55 g), and the mixture was stirred overnight at 80° C. under argonatmosphere. The reaction mixture was allowed to be cooled to roomtemperature, water and ethyl acetate were added thereto, and the mixturewas partitioned. The organic layer was washed with water and saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.48 g).

MS: [M−H]⁺ 286.1.

C) methyl3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl2-hydroxy-3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)benzoate (0.48 g)in DMF (9.50 mL) were added sodium hydride (0.08 g) andN-phenylbis(trifluoromethanesulfonimide) (0.66 g) under ice-cooling, andthe mixture was stirred at room temperature for 2.5 hr. To the reactionmixture was added 1N hydrochloric acid, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium bicarbonate solution and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.70g).

MS: [M+H]⁺ 418.1.

D) methyl 3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)-2-vinylbenzoate

To a solution of methyl3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)-2-((trifluoromethyl)sulfonyl)oxy)benzoate(0.70 g) in DMF (14.0 mL) were added tributylvinyltin (0.80 g),trans-dichlorobis(triphenylphosphine)palladium(II) (0.06 g) and lithiumchloride (0.53 g), and the mixture was stirred at 90° C. for 1 hr underargon atmosphere. To the reaction mixture was added aqueous potassiumfluoride solution, and the precipitated insoluble substance was removedby filtration through Celite. The filtrate was diluted with ethylacetate, and the mixture was washed with water and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.44 g).

MS: [M+H]⁺ 296.1.

E) methyl 2-formyl-3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)benzoate

To a solution of methyl3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)-2-vinylbenzoate (0.44 g)in a mixed solvent of acetone (5.40 mL)-acetonitrile (5.40 mL)-water(5.40 mL) were added osmium oxide (fixed catalyst I) (0.19 g) and sodiumperiodate (1.59 g), and the mixture was stirred overnight at roomtemperature. The reaction mixture was filtered, and the filtrate wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure to give the title compound(0.44 g) as a crude product. This compound was used in the next stepwithout an additional purification.

MS: [M+H]⁺ 298.1.

F)2-((1S,2S)-2-hydroxycyclohexyl)-4,5-dimethyl-6-((6-methylpyridin-3-yl)methyl)isoindolin-1-one

To a solution of methyl2-formyl-3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)benzoate (0.15 g)in THF (2.90 mL) were added (1S,2S)-aminocyclohexanol (0.06 g) andanhydrous magnesium sulfate (0.11 g), and the mixture was stirred atroom temperature for 6 hr. The insoluble substance was removed byfiltration, the filtrate was concentrated, and the residue was dilutedwith methanol (2.90 mL)-THF (2.90 mL). Sodium triacetoxyborohydride(0.21 g) was added thereto, and the mixture was stirred overnight atroom temperature. The reaction mixture was diluted with ethyl acetate,and the mixture was washed with water and saturated brine. The organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (methanol/ethyl acetate) to give the titlecompound (0.05 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.22-1.38 (3H, m), 1.48-1.72 (4H, m),1.90-2.01 (1H, m), 2.19 (3H, s), 2.22 (3H, s), 2.41 (3H, s), 3.55-3.66(1H, m), 3.81 (1H, td, J=10.7, 4.1 Hz), 4.05 (2H, s), 4.35 (2H, s), 4.71(1H, d, J=5.7 Hz), 7.14 (1H, d, J=7.9 Hz), 7.27-7.38 (2H, m), 8.29 (1H,d, J=1.9 Hz).

Example 25-2

2-((1S,2S)-2-Hydroxycyclohexyl)-4,5-dimethyl-6-((6-methylpyridin-3-yl)methyl)isoindolin-1-onewas also synthesized by the following method.

A) 5-(chloromethyl)-2-methylpyridine hydrochloride

To a solution of (6-methylpyridin-3-yl)methanol (1.24 g) in THF (12.4mL) was added thionyl chloride (1.10 mL) under ice-cooling, and themixture was stirred overnight at room temperature. The reaction mixturewas concentrated under reduced pressure, and the obtained residue wassuspended in ethyl acetate. The precipitate was collected by filtration,and washed with ethyl acetate-hexane to give the title compound (1.64g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.72 (3H, s), 4.93 (2H, s), 7.86 (1H, d,J=8.1 Hz), 8.44 (1H, dd, J=8.2, 2.0 Hz), 8.85 (1H, d, J=1.9 Hz).

B) methyl2-hydroxy-3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)benzoate

To a solution of methyl2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(2.00 g) in a mixed solvent of DME (30.0 mL)-water (10.0 mL) were added5-(chloromethyl)-2-methylpyridine hydrochloride (1.22 g),tetrakis(triphenylphosphine)palladium(0) (0.38 g) and sodium carbonate(2.11 g), and the mixture was stirred overnight at 80° C. under argonatmosphere. The reaction mixture was allowed to be cooled to roomtemperature, water and ethyl acetate were added thereto, and the mixturewas partitioned. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (1.57g).

MS: [M−H]⁺ 286.1.

C) methyl3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a mixture of methyl2-hydroxy-3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)benzoate (1.57g), sodium hydride (0.26 g) and DMF (32.0 mL) was addedN-phenylbis(trifluoromethanesulfonimide) (2.16 g) under ice-cooling, andthe mixture was stirred at room temperature for 2 hr. To the reactionmixture was added 1N hydrochloric acid, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium bicarbonate solution and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.76g).

MS: [M+H]⁺ 418.1.

D) methyl 3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)-2-vinylbenzoate

To a solution of methyl3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate(0.76 g) in DMF (16.0 mL) were added tributylvinyltin (0.87 g),bis(triphenylphosphine)palladium(II) dichloride (0.06 g) and lithiumchloride (0.57 g), and the mixture was stirred at 90° C. for 1.5 hrunder argon atmosphere. To the reaction mixture was added aqueouspotassium fluoride solution, and the precipitated insoluble substancewas removed by filtration through Celite. The filtrate was diluted withethyl acetate, and the mixture was washed with saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.50 g).

MS: [M+H]⁺ 296.2.

E) methyl 2-formyl-3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)benzoate

To a solution of methyl3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)-2-vinylbenzoate (0.49 g)in a mixed solvent of acetone (6.10 mL)-acetonitrile (6.10 mL)-water(6.10 mL) were added osmium oxide (fixed catalyst I) (0.21 g) and sodiumperiodate (1.79 g), and the mixture was stirred overnight at roomtemperature. The reaction mixture was filtered, and the filtrate wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure to give the title compound(0.47 g) as a crude product. This compound was used in the next stepwithout an additional purification.

MS: [M+H]⁺ 298.1.

F)2-((1S,2S)-2-hydroxycyclohexyl)-4,5-dimethyl-6-((6-methylpyridin-3-yl)methyl)isoindolin-1-one

To a solution of methyl2-formyl-3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)benzoate (0.47 g)in THF (9.40 mL) were added (1S,2S)-aminocyclohexanol (0.18 g) andanhydrous magnesium sulfate (0.37 g), and the mixture was stirred atroom temperature for 6 hr. The insoluble substance was removed byfiltration, the filtrate was concentrated, and the residue was dilutedwith methanol (9.40 mL)-THF (9.40 mL). Sodium triacetoxyborohydride(0.67 g) was added thereto, and the mixture was stirred overnight atroom temperature. The reaction mixture was diluted with ethyl acetate,and the mixture was washed with water and saturated brine. The organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (methanol/ethyl acetate) to give the titlecompound (0.20 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.22-1.39 (3H, m), 1.47-1.75 (4H, m),1.89-2.02 (1H, m), 2.20 (3H, s), 2.22 (3H, s), 2.41 (3H, s), 3.61 (1H,dd, J=10.0, 5.1 Hz), 3.74-3.88 (1H, m), 4.05 (2H, s), 4.35 (2H, s), 4.69(1H, d, J=5.5 Hz), 7.14 (1H, d, J=7.9 Hz), 7.29 (1H, s), 7.35 (1H, dd,J=7.9, 2.3 Hz), 8.29 (1H, d, J=1.9 Hz).

X-ray powder diffraction pattern with specific peaks at d value (ord-spacing)=18.5, 10.3, 9.2, 7.0, 5.3, 5.1, 4.7, 4.4, 4.3 and 4.2 Å.

Example 261,5-anhydro-2-(6-(4-cyano-3-fluorobenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,4-dideoxy-L-threo-pentitolA) methyl 5-(4-cyano-3-fluorobenzyl)-2-hydroxy-3,4-dimethylbenzoate

To a mixture of methyl2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(1.07 g), 4-(chloromethyl)-2-fluorobenzonitrile (0.89 g), 2 mol/Laqueous sodium carbonate solution (3.50 mL) and DME (20.0 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.14 g) under argon atmosphere, and the mixturewas stirred overnight at 80° C., and then at room temperature forweekend. To the reaction mixture was added water at room temperature,and the mixture was extracted with ethyl acetate. The organic layer wasseparated, washed with water and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (1.10g).

MS: [M+H]⁺ 312.0.

B) methyl 5-(4-cyano-3-fluorobenzyl)-3,4-dimethyl-2-vinylbenzoate

A solution of methyl5-(4-cyano-3-fluorobenzyl)-2-hydroxy-3,4-dimethylbenzoate (1.10 g) inDMF (20.0 mL) was ice-cooled under argon atmosphere, sodium hydride(0.15 g) was added thereto, and the mixture was stirred at roomtemperature for 30 min. To this reaction mixture was addedN-phenylbis(trifluoromethanesulfonimide) (1.51 g) under ice-cooling, andthe mixture was stirred at room temperature for 1.5 hr. To the reactionmixture was added 1N hydrochloric acid under ice-cooling, and themixture was extracted with ethyl acetate. The organic layer wasseparated, washed with water and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained crude methyl5-(4-cyano-3-fluorobenzyl)-3,4-dimethyl-2-{[(trifluoromethyl)sulfonyl]oxy}benzoatewas used in the next step without an additional purification.

To a mixture of the above-mentioned compound, lithium chloride (1.04 g),tributylvinyltin (1.54 mL) and DMF (20.0 mL) was addedtrans-dichlorobis(triphenylphosphine)palladium(II) (0.12 g) under argonatmosphere, and the mixture was stirred at 90° C. for 2 hr, and thenovernight at room temperature. To the reaction mixture was addedtributylvinyltin (1.54 mL) under argon atmosphere, and the mixture wasstirred at 90° C. for 2 hr. To the reaction mixture were added ethylacetate and 10% aqueous potassium fluoride solution, and theprecipitated insoluble substance was removed by filtration throughCelite. The filtrate was extracted with ethyl acetate, the organic layerwas separated, washed with water and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.67g).

MS: [M+H]⁺ 322.1.

C) methyl 5-(4-cyano-3-fluorobenzyl)-2-formyl-3,4-dimethylbenzoate

To a mixture of methyl5-(4-cyano-3-fluorobenzyl)-3,4-dimethyl-2-vinylbenzoate (0.67 g) andsodium periodate (2.22 g) in acetone (15.0 mL)-acetonitrile (15.0mL)-water (15.0 mL) was added osmium oxide (fixed catalyst I) (0.26 g),and the mixture was stirred overnight at room temperature under argonatmosphere. The reaction mixture was filtered, and the filtrate wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.25 g).

MS: [M+H]⁺ 326.1.

D)1,5-anhydro-2-(6-(4-cyano-3-fluorobenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,4-dideoxy-L-threo-pentitol

To a solution of methyl5-(4-cyano-3-fluorobenzyl)-2-formyl-3,4-dimethylbenzoate (0.25 g) in THF(5.00 mL) was added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.09 g),and the mixture was stirred overnight at room temperature under argonatmosphere. The reaction mixture was concentrated, and the residue wasdiluted with acetic acid (5.00 mL). Then, sodium triacetoxyborohydride(0.24 g) was added thereto and the mixture was stirred at roomtemperature for 2 hr under argon atmosphere. To the reaction mixture wasadded saturated aqueous sodium bicarbonate, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane,methanol/ethyl acetate) to give the title compound (0.16 g).

¹H NMR (300 MHz, CDCl₃) δ 1.73-1.89 (1H, m), 2.08-2.18 (4H, m), 2.26(3H, s), 2.56 (1H, d, J=5.7 Hz), 3.45-3.63 (2H, m), 3.99-4.19 (6H, m),4.27-4.53 (2H, m), 6.89 (1H, d, J=10.0 Hz), 7.00 (1H, d, J=7.9 Hz),7.47-7.55 (2H, m).

Example 38rac-2-(trans-2-methoxycyclohexyl)-5-methyl-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-one

To a solution ofrac-2-(trans-2-hydroxycyclohexyl)-5-methyl-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-one(0.06 g) (obtained in the same manner as in Example 8) in DMF (1.20 mL)was added sodium hydride (9.0 mg) under ice-cooling, and the mixture wasstirred for 20 min. Methyl iodide (0.05 mL) was added thereto at thesame temperature, and the mixture was stirred at room temperature fortwo nights under nitrogen atmosphere. To this reaction mixture was addedsodium hydride (9.0 mg) under ice-cooling, and the mixture was stirredat room temperature for 7 hr. The reaction mixture was poured into waterunder ice-cooling, and the mixture was extracted with ethyl acetate. Theorganic layer was separated, washed with saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) and then HPLC (water/acetonitrile)to give the title compound (0.004 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.29-1.46 (3H, m), 1.63-1.96 (4H, m),2.19-2.30 (1H, m), 2.31 (3H, s), 3.27 (3H, s), 3.38-3.51 (1H, m),4.04-4.17 (3H, m), 4.34 (2H, s), 6.44 (1H, t, J=2.1 Hz), 7.17-7.25 (3H,m), 7.58 (2H, d, J=8.7 Hz), 7.66-7.74 (2H, m), 7.88 (1H, d, J=2.4 Hz).

Example 575-ethyl-6-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-(tetrahydrofuran-2-ylmethyl)isoindolin-1-oneA) methyl 4-bromo-2-hydroxybenzoate

To a solution of 4-bromo-2-hydroxybenzoic acid (15.0 g) in methanol (150mL) was added dropwise thionyl chloride (10.1 mL) under ice-cooling. Thereaction solution was stirred at 70° C. overnight under argonatmosphere. The reaction solution was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (14.2g).

¹H NMR (300 MHz, DMSO-d₆) δ 3.88 (3H, s), 7.10-7.18 (1H, m), 7.21-7.28(1H, m), 7.69 (1H, d, J=8.3 Hz), 10.65 (1H, s).

B) methyl 2-hydroxy-4-vinylbenzoate

To a solution of methyl 4-bromo-2-hydroxybenzoate (3.0 g) in DMF (50.0mL) were added tributylvinyltin (6.18 g),bis(triphenylphosphine)palladium(II) chloride (0.46 g) and lithiumchloride (4.07 g), and the mixture was stirred at 90° C. for 2 hr underargon atmosphere. To the reaction mixture was added aqueous potassiumfluoride solution, and the precipitated insoluble substance was removedby filtration through Celite. The filtrate was diluted with ethylacetate, and the mixture was washed with water and saturated brine. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound. This compound was used in the next step without anadditional purification.

C) methyl 4-ethyl-2-hydroxybenzoate

To a solution of methyl 2-hydroxy-4-vinylbenzoate (2.31 g) in ethanol(25.0 mL) was added palladium-carbon (1.38 g), and the mixture wasstirred overnight at room temperature under hydrogen atmosphere. Theinsoluble substance was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby NH silica gel column chromatography (ethyl acetate/hexane) to givethe title compound (1.43 g).

MS: [M+H]⁺ 181.1.

D) methyl 5-bromo-4-ethyl-2-hydroxybenzoate

To a solution of methyl 4-ethyl-2-hydroxybenzoate (1.43 g) in aceticacid (15.0 mL) was added bromine (1.40 g) under ice-cooling, and themixture was stirred at room temperature for 2 hr under argon atmosphere.To the reaction mixture was added water, the resulting solid wascollected by filtration, and dried under reduced pressure to give thetitle compound (2.21 g) as a mixture with methyl3,5-dibromo-4-ethyl-2-hydroxybenzoate (2:1). This compound was used inthe next step without an additional purification.

E) methyl4-ethyl-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

A mixture of the mixture (1.00 g) of methyl5-bromo-4-ethyl-2-hydroxybenzoate and methyl3,5-dibromo-4-ethyl-2-hydroxybenzoate, bis(pinacolato)diboron (1.47 g),potassium acetate (1.14 g),trans-dichlorobis(triphenylphosphine)palladium(II) (0.14 g) and toluene(20.0 mL) was stirred overnight at 100° C. under argon atmosphere. Thereaction mixture was diluted with ethyl acetate, and the mixture waswashed with saturated brine. The organic layer was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.82 g). This compound wasused in the next step without an additional purification.

MS: [M+H]⁺ 307.2.

F) methyl4-ethyl-2-hydroxy-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)benzoate

A mixture of methyl4-ethyl-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(0.41 g), 3-(4-(bromomethyl)phenyl)-1-methyl-1H-pyrazole (0.44 g),sodium carbonate (0.28 g), tetrakis(triphenylphosphine)palladium(0)(0.15 g), DME (15.0 mL) and water (5.0 mL) was stirred overnight at 90°C. under argon atmosphere. The reaction mixture was diluted with ethylacetate, and the mixture was washed with saturated brine. The organiclayer was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.26 g).

MS: [M+H]⁺ 351.1.

G) methyl4-ethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of methyl4-ethyl-2-hydroxy-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)benzoate (0.26g) and N-phenylbis(trifluoromethanesulfonimide) (0.29 g) in DMF (3.00mL) was added sodium hydride (0.04 g) under ice-cooling, and the mixturewas stirred at room temperature for 1 hr under argon atmosphere. Thereaction mixture was diluted with ethyl acetate, and the mixture waswashed with saturated brine. The organic layer was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.32 g).

MS: [M+H]⁺ 483.1.

H) methyl 4-ethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-vinylbenzoate

A mixture of methyl4-ethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate(0.32 g), tributylvinyltin (0.32 g),trans-dichlorobis(triphenylphosphine)palladium(II) (0.02 g), lithiumchloride (0.21 g) and DMF (6.00 mL) was stirred at 90° C. for 2 hr underargon atmosphere. To the reaction mixture was added aqueous potassiumfluoride solution, and the precipitated insoluble substance was removedby filtration. The filtrate was diluted with ethyl acetate, and themixture was washed with saturated brine. The organic layer was driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.21g). This compound was used in the next step without an additionalpurification.

I) methyl4-ethyl-2-formyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)benzoate

A mixture of methyl4-ethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-vinylbenzoate (0.21 g),osmium oxide (fixed catalyst I) (0.08 g) and sodium periodate (0.64 g)in acetone (4.00 mL)-acetonitrile (4.00 mL)-water (4.00 mL) was stirredovernight at room temperature. The insoluble substance was removed byfiltration, the filtrate was diluted with ethyl acetate, and the mixturewas washed with saturated brine. The organic layer was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure to give the title compound (0.21 g) as a crude product. Thiscompound was used in the next step without an additional purification.

J)5-ethyl-6-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-((tetrahydrofuran-2-yl)methyl)isoindolin-1-one

A mixture of methyl4-ethyl-2-formyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)benzoate (0.11g), (tetrahydrofuran-2-yl)methanamine (0.03 g) and anhydrous magnesiumsulfate (0.07 g) in THF (3.00 mL) was stirred overnight at roomtemperature. The insoluble substance was removed by filtration, and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with acetic acid (3.00 mL), sodium triacetoxyborohydride (0.09g) was added thereto, and the mixture was stirred overnight at roomtemperature. The reaction mixture was neutralized with saturated aqueoussodium bicarbonate solution, and the mixture was extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane), and crystallized from ethylacetate/hexane to give the title compound (0.03 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.11 (3H, t, J=7.6 Hz), 1.47-1.63 (1H, m),1.74-2.00 (3H, m), 2.69 (2H, q, J=7.7 Hz), 3.44-3.67 (3H, m), 3.72-3.82(1H, m), 3.86 (3H, s), 3.98-4.06 (1H, m), 4.09 (2H, s), 4.50 (2H, d,J=4.5 Hz), 6.62 (1H, d, J=2.3 Hz), 7.15 (2H, d, J=8.3 Hz), 7.42 (2H, s),7.63-7.75 (3H, m).

Example 964-fluoro-5-methoxy-6-(4-(1H-pyrazol-1-yl)benzyl)-2-(tetrahydrofuran-2-ylmethyl)isoindolin-1-oneA) 2-fluoro-3-methoxyphenol

To a solution of 2-fluoro-3-methoxyphenylboronic acid (30.4 g) in THF(300 mL) was added dropwise aqueous hydrogen peroxide (100 mL, 30% wt inwater), and the mixture was heated with reflux for 1 hr. The reactionmixture was allowed to be cooled to room temperature, saturated aqueoussodium sulfite was added thereto, and the mixture was extracted withethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by combi flash (petroleum ether/ethyl acetate) togive the title compound (24.8 g).

¹H NMR (400 MHz, CDCl₃) δ 3.88 (3H, s), 5.23 (1H, brs), 6.53 (1H, t,J=8.4 Hz), 6.62 (1H, t, J=8.4 Hz), 6.93 (1H, td, J=8.4, 2.0 Hz).

B) 3-fluoro-2-hydroxy-4-methoxybenzaldehyde

To a solution of 2-fluoro-3-methoxyphenol (22.0 g) and triethylamine(93.9 g) in dichloroethane (250 mL) was added magnesium chloride (71.7g), and the mixture was stirred at 40° C. for 1 hr. To this mixture wasadded paraformaldehyde (46.5 g), and the mixture was stirred for 16 hr.The reaction solution was allowed to be cooled to room temperature, 1Nhydrochloric acid was added thereto, and the mixture was extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by combi flash (petroleum ether/ethyl acetate) togive the title compound (26.0 g).

¹H NMR (400 MHz, DMSO-d₆) δ 3.98 (3H, s), 6.64 (1H, dd, J=8.8, 6.8 Hz),7.32 (1H, dd, J=8.8, 1.6 Hz), 9.77 (1H, d, J=2.0 Hz). One active protonwas not observed.

C) 3-fluoro-2-hydroxy-4-methoxybenzoic acid

To a mixture of 3-fluoro-2-hydroxy-4-methoxybenzaldehyde (10.0 g) andsodium dihydrogenphosphate (22.9 g) in DMSO (100 mL) and water (25.0 mL)was added dropwise an aqueous solution (30.0 mL) of sodium chlorite(14.5 g), and the mixture was stirred at 20° C. for 16 hr. The solventwas evaporated under reduced pressure, the residue was diluted withwater, and the mixture was extracted with ethyl acetate (×6). Theorganic layer was washed with saturated brine, and dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure togive the title compound (7.42 g).

¹H NMR (400 MHz, DMSO-d₆) δ 3.89 (3H, s), 6.75 (1H, t, J=8.4 Hz), 7.59(1H, dd, J=9.2, 2.0 Hz). Two active protons were not observed.

D) 5-bromo-3-fluoro-2-hydroxy-4-methoxybenzoic acid

To a solution of 3-fluoro-2-hydroxy-4-methoxybenzoic acid (7.30 g) inDMF (70.0 mL) was added NBS, and the mixture was stirred at 25° C. for 2hr. The solvent was evaporated under reduced pressure, and the residuewas diluted with ethyl acetate. The mixture was washed with water andsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure to give the title compound(8.86 g).

¹H NMR (400 MHz, DMSO-d₆) δ 4.00 (3H, s), 7.74 (1H, d, J=2.0 Hz). Twoactive protons were not observed and it contained some impurity.

E) methyl 5-bromo-3-fluoro-2-hydroxy-4-methoxybenzoate

To a solution of 5-bromo-3-fluoro-2-hydroxy-4-methoxybenzoic acid (0.70g) in methanol (15.0 mL) was added dropwise thionyl chloride (0.39 mL)under ice-cooling. The reaction solution was stirred at 70° C. for 15 hrunder argon atmosphere, and then overnight at room temperature. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.52 g).

¹H NMR (300 MHz, CDCl₃) δ 3.97 (3H, s), 4.12 (3H, d, J=3.0 Hz), 7.82(1H, d, J=2.3 Hz), 10.84 (1H, s).

F) methyl3-fluoro-2-hydroxy-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate

To a solution of methyl 5-bromo-3-fluoro-2-hydroxy-4-methoxybenzoate(0.52 g) in DME (10.0 mL) were added bis(pinacolato)diboron (0.71 g),potassium acetate (0.55 g) and[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane adduct (0.08 g), and the mixture was stirred at 80° C.for 5 hr under argon atmosphere. The reaction mixture was allowed to becooled to room temperature, water was added thereto, and the mixture wasdiluted with ethyl acetate. The organic layer was washed with water andsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure to give methyl3-fluoro-2-hydroxy-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoateas a crude product. To a solution of the above-mentioned crude productin DME (10.0 mL) were added 1-(4-(bromomethyl)phenyl)-1H-pyrazole (0.44g), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane adduct (0.08 g) and 2M aqueous sodium carbonate solution(1.86 mL), and the mixture was stirred at 80° C. overnight under argonatmosphere. The reaction mixture was allowed to be cooled to roomtemperature, water was added thereto, and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.21 g).

¹H NMR (300 MHz, CDCl₃) δ 3.92 (2H, s), 3.93 (3H, s), 3.94-3.97 (3H, m),6.46 (1H, t, J=2.2 Hz), 7.24 (2H, s), 7.41 (1H, d, J=2.1 Hz), 7.61 (2H,d, J=8.5 Hz), 7.72 (1H, d, J=1.5 Hz), 7.88-7.92 (1H, m), 10.81 (1H, s).

G) methyl2-ethenyl-3-fluoro-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate

To a solution of methyl3-fluoro-2-hydroxy-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate (0.21g) in DMF (5.00 mL) was added sodium hydride (0.03 g) under ice-cooling,and the mixture was stirred at room temperature for 0.5 hr under argonatmosphere. To the reaction mixture was addedN-phenylbis(trifluoromethanesulfonimide) (0.23 g), and the mixture wasstirred at room temperature for 0.5 hr under argon atmosphere. To thereaction mixture was added 1N hydrochloric acid, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure to give methyl3-fluoro-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]-2-{[(trifluoromethyl)sulfonyl]oxy}benzoateas a crude product. To a mixture of the obtained crude product,tributylvinyltin (0.26 mL) and lithium chloride (0.19 g) in DMF (5.00mL) was added bis(triphenylphosphine)palladium(II) dichloride (0.02 g),and the mixture was stirred at 90° C. for 2 hr under argon atmosphere.To the reaction mixture was added 10% aqueous potassium fluoridesolution, and the precipitated insoluble substance was removed byfiltration through Celite. To the filtrate was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.12 g).

MS: [M+H]⁺ 367.2.

H)4-fluoro-5-methoxy-6-(4-(1H-pyrazol-1-yl)benzyl)-2-(tetrahydrofuran-2-ylmethyl)isoindolin-1-one

To a solution of methyl2-ethenyl-3-fluoro-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate (0.12g) in a mixed solvent of acetone (2.00 mL)-acetonitrile (2.00 mL)-water(2.00 mL) were added osmium oxide (fixed catalyst I) (0.04 g) and sodiumperiodate (0.35 g), and the mixture was stirred at room temperature for3 hr under argon atmosphere. The reaction mixture was filtered, and thefiltrate was concentrated under reduced pressure. To the residue wasadded water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure togive methyl3-fluoro-2-formyl-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate as acrude product. The obtained crude product (20% v/v) was dissolved in THF(2.00 mL), (tetrahydrofuran-2-yl)methanamine (0.006 g) was addedthereto, and the mixture was stirred at room temperature for 1 hr. Thereaction solution was concentrated under reduced pressure, and theresidue was diluted with acetic acid (1.00 mL). Sodiumtriacetoxyborohydride (0.03 g) was added thereto, and the mixture wasstirred overnight at room temperature. The reaction mixture wasneutralized with saturated aqueous sodium hydrogencarbonate solution,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by HPLC (water/acetonitrile,containing 0.1% TFA). The fractions were combined, saturated aqueoussodium hydrogencarbonate solution was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reduced pressureto give the title compound (2.90 mg).

MS: [M+H]⁺ 422.2.

Example 113rac-3-fluoro-4-((2-(trans-4-hydroxytetrahydro-2H-pyran-3-yl)-6,7-dimethyl-3-oxoisoindolin-5-yl)methyl)benzamide

To a mixture ofrac-3-fluoro-4-((2-(trans-4-hydroxytetrahydro-2H-pyran-3-yl)-6,7-dimethyl-3-oxoisoindolin-5-yl)methyl)benzonitrile(0.08 g) and potassium carbonate (0.08 g) in DMSO (2.00 mL) was added35% aqueous hydrogen peroxide (0.17 mL) under ice-cooling, and themixture was stirred at room temperature for 3 hr. The reaction solutionwas diluted with water, and the mixture was extracted with ethylacetate-THF. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was washed with ethyl acetate togive the title compound (0.07 g).

MS: [M+H]⁺ 413.2.

The compounds of Examples 27 to 37, 39 to 56, 58 to 95, 97 to 112 and114 to 168 in Table 1 were synthesized according to the method shown inthe above-mentioned Examples or a method analogous thereto. The Examplecompounds are shown in Table 1. MS in the tables means actual measuredvalue.

TABLE 1-1 Ex. structure No. IUPAC Name formula MS 1 rac-2-(trans-2-hydroxycyclohexyl)-6-((6- (1-methyl-1H-pyrazol-4- yl)pyridin-3-yl)methyl)isoindolin-1-one

403.2 2 rac-5-chloro-2-(trans-2- hydroxycyclohexyl)-6-(4- (1H-pyrazol-1-yl)benzyl)isoindolin-1-one

422.1 3 rac-2-(trans-2- hydroxycyclohexyl)-5-methoxy-6-(4-(1H-pyrazol-1- yl)benzyl)isoindolin-1-one

418.2 4 2-((1S,2S)-2- hydroxycyclopentyl)-5- methyl-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-one

388.2 5 rac-6-((6-(1,3-dimethyl-1H- pyrazol-4-yl)pyridin-3-yl)methyl)-2-(trans-2- hydroxycyclohexyl)-5- methylisoindolin-1-one

431.2

TABLE 1-2 Ex. structure No. IUPAC Name formula MS  6 rac-2-(trans-2-hydroxycyclohexyl)-5-methyl-6- ((2′-methyl-2,4′-bipyridin-5-yl)methyl)isoindolin-1-one

428.2  7 3-fluoro-2-(5-methyl-1-oxo-6-(4- (1H-pyrazol-1-yl)benzyl)-1,3-dihydro-2H-isoindol-2- yl)benzonitrile

423.1  8 5-methyl-6-(4-(1H-pyrazol-1- yl)benzyl)-2-(tetrahydro-2H-pyran-4-yl)isoindolin-1-one

388.2  9 rac-5-cyclopropyl-2-(trans-2- hydroxycyclopentyl)-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin- 1-one

414.2 10 rac-4-chloro-2-(trans-2- hydroxycyclohexyl)-6-(4-(1H-pyrazol-1-yl)benzyl)-5- (trifluoromethyl)isoindolin-1- one

490.1

TABLE 1-3 Ex. structure No. IUPAC Name formula MS 11 rac-2-(trans-2-hydroxycyclohexyl)-4- methyl-1-oxo-6-(4-(1H- pyrazol-1-yl)benzyl)isoindoline-5- carbonitrile

427.2 12 rac-4-chloro-2-(trans-2- hydroxycyclohexyl)-5-methoxy-6-(4-(1H-pyrazol-1- yl)benzyl)isoindolin-1-one

452.1 13 2-((1S,2S)-2- hydroxycyclopentyl)-4,5-dimethyl-6-(4-(1-methyl-1H- pyrazol-3- yl)benzyl)isoindolin-1-one

416.2 14 4,5-dimethyl-6-(4-(1- methyl-1H-1,2,3-triazol-4-yl)benzyl)-2-((2S)- tetrahydrofuran-2- ylmethyl)isoindolin-1-one

417.1 15 2-(2-hydroxy-2- methylpropyl)-4,5-dimethyl- 6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-one

390.1

TABLE 1-4 Ex. structure No. IUPAC Name formula MS 166-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-2-((1S,2S)-2-hydroxycyclopentyl)-4,5- dimethylisoindolin-1-one

420.1 17 1,5-anhydro-2-(6-(4-chlorobenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,4-dideoxy-L-threo-pentitol

386.0 18 2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-6-(4-methoxybenzyl)-4,5-dimethyl-2,3-dihydro-1H-isoindol-1-one Alias;1,5-anhydro-2,4-dideoxy-2-(6-(4- methoxybenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo- pentitol

382.2 19 1,5-anhydro-2,4-dideoxy-2-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-4,5- dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

427.1 20 4-fluoro-2-[(3S,4S)-4- hydroxytetrahydro-2H-pyran-3-yl]-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]- 2,3-dihydro-1H-isoindol-1-oneAlias; 1,5-anhydro-2,4-dideoxy-2-(4-fluoro-5-methyl-1-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)-1,3-dihydro-2H-isoindol-2- yl)-L-threo-pentitol

422.1

TABLE 1-5 Ex. No. IUPAC Name structure formula MS 21 1,5-anhydro-2,4-dideoxy-2-(5-methyl- 1-oxo-6-(4-(1H- pyrazol-1-yl)benzyl)-1,3-dihydro-2H- isoindol-2-yl)-L- threo-pentitol

404.1 22 1,5-anhydro-2,4- dideoxy-2-(6-(4- (difluoro- methoxy)benzyl)-4,5-dimethyl-1- oxo-1,3-dihydro- 2H-isoindol-2-yl)- L-threo-pentitol

418.0 23 1,5-anhydro-2,4- dideoxy-2-(6-(4- fluoro-3- methoxybenzyl)-4,5-dimethyl-1- oxo-1,3-dihydro- 2H-isoindol-2-yl)- L-threo-pentitol

400.1 24 1,5-anhydro-2- (4-chloro-6-(4- methoxybenzyl)- 5-methyl-1-oxo-1,3-dihydro-2H- isoindol-2-yl)-2,4- dideoxy-L-threo- pentitol

402.1 25 2-((1S,2S)-2- hydroxycyclo- hexyl)-4,5- dimethyl-6-((6-methylpyridin-3- yl)methyl)iso- indolin-1-one

365.2

TABLE 1-6 Ex. No. IUPAC Name structure formula MS 26 1,5-anhydro-2-(6-(4-cyano-3- fluorobenzyl)- 4,5-dimethyl-1- oxo-1,3-dihydro-2H-isoindol-2- yl)-2,4-dideoxy- L-threo-pentitol

395.1 27 2-(2- fluorophenyl)- 6-((6-(1-methyl- 1H-pyrazol-4-yl)pyridin-3- yl)meth- yl)isoindolin-1- one

399.1 28 rac-2-(trans-2- hydroxycyclo- hexyl)-4,5- dimethyl-6-((6-(1-methyl-1H- pyrazol-4- yl)pyridin-3- yl)methyl)iso- indolin-1-one

431.2 29 rac-2-(trans-2- hydroxycyclo- hexyl)-4,5- dimethyl-6-(4-(1H-pyrazol-1- yl)benzyl)iso- indolin-1-one

416.2 30 rac-2-(trans-2- hydroxycyclo- hexyl)-4-methyl-6-(4-(1H-pyrazol- 1-yl)ben- zyl)isoindolin-1- one

402.2

TABLE 1-7 Ex. No. IUPAC Name structure formula MS 31 rac-2-(trans-2-hydroxycyclo- pentyl)-4-methyl- 6-(4-(1H-pyrazol- 1-yl)ben-zyl)isoindolin-1- one

388.1 32 rac-2-(trans-2- hydroxycyclo- hexyl)-5-methyl-6-(4-(1H-pyrazol- 1-yl)ben- zyl)isoindolin-1- one

402.2 33 rac-2-(trans-2- hydroxycyclo- pentyl)-5-methyl-6-(4-(1H-pyrazol- 1-yl)benzyl)iso- indolin-1-one

388.2 34 rac-2-(trans-2- hydroxycyclo- pentyl)-4,5- dimethyl-6-(4-(1H-pyrazol-1- yl)benzyl)iso- indolin-1-one

402.1 35 rac-2-(trans-4- hydroxytetra- hydro-2H-pyran- 3-yl)-4,5-dimethyl-6-(4- (1H-pyrazol-1- yl)benzyl)-2,3- dihydro-1H- isoindol-1-one

418.2

TABLE 1-8 Ex. No. IUPAC Name structure formula MS 36 5-methyl-6-(4-(1H-pyrazol-1- yl)benzyl)-2- (tetrahydrofuran- 2-ylmethyl)iso-indolin-1-one

388.2 37 2-(1-(hydroxy- methyl)cyclopen- tyl)-5-methyl-6-(4-(1H-pyrazol- 1-yl)benzyl)iso- indolin-1-one

402.2 38 rac-2-(trans-2- methoxycyclo- hexyl)-5-methyl-6-(4-(1H-pyrazol- 1-yl)benzyl)iso- indolin-1-one

416.2 39 2-((1R,2R)-2- hydroxycyclo- pentyl)-5-methyl- 6-(4-(1H-pyrazol-1-yl)benzyl)iso- indolin-1-one

388.2 40 rac-6-((6-(1,3- dimethyl-1H- pyrazol-4- yl)pyridin-3-yl)methyl)-2- (trans-2-hydroxy- cyclopentyl)-5- methylisoindolin- 1-one

417.1

TABLE 1-9 Ex. No. IUPAC Name structure formula MS 41 rac-2-(trans-2-hydroxycyclo- pentyl)-5- methyl-6-((2′- methyl-2,4′- bipyridin-5-yl)methyl)iso- indolin-1-one

414.2 42 rac-2-(trans-2- hydroxycyclo- hexyl)-5-methyl- 6-((6-(1-methyl-1H-pyrazol-3- yl)pyridin-3- yl)meth- yl)isoindolin-1- one

417.1 43 rac-2-(trans-2- hydroxycyclo- pentyl)-5-methyl-6-((6-(1-methyl- 1H-pyrazol-3- yl)pyridin-3- yl)methyl)iso-indolin-1-one

403.2 44 rac-6-(2,4- difluorobenzyl)- 2-(trans-2- hydroxycyclo-hexyl)-5-methyl- isoindolin-1-one

372.2 45 rac-6-(2,4- difluorobenzyl)- 2-(trans-2- hydroxycyclo-pentyl)-5-methyl- isoindolin-1-one

358.1

TABLE 1-10 Ex. No. IUPAC Name structure formula MS 46 2-((1R,2S)-2-hydroxycyclo- pentyl)-5-methyl- 6-(4-(1H-pyrazol- 1-yl)ben-zyl)isoindolin-1- one

388.2 47 rac-2-(trans-2- hydroxycyclo- hexyl)-5-methyl- 6-(4-(1-methyl-1H-1,2,3-triazol- 4-yl)ben- zyl)isoindolin-1- one

417.1 48 rac-2-(trans-2- hydroxycyclo- pentyl)-5-methyl- 6-(4-(1-methyl-1H-1,2,3-triazol- 4-yl)ben- zyl)isoindolin-1- one

403.2 49 5-methyl-6-(4-(1- methyl-1H-1,2,3- triazol-4- yl)benzyl)-2-(tetrahydrofuran- 2-ylmethyl)iso- indolin-1-one

403.2 50 5-methyl-6-(4- (1H-pyrazol-1- yl)benzyl)-2- (tetrahydro-2H-pyran-3- yl)isoindolin-1- one

388.2

TABLE 1-11 Ex. No. IUPAC Name structure formula MS 51 rac-2-(trans-2-hydroxycyclo- pentyl)-5-methyl- 6-(4-(1-methyl- 1H-pyrazol-3- yl)ben-zyl)isoindolin-1- one

402.1 52 5-methyl-6-(4- (1-methyl-1H- pyrazol-3- yl)benzyl)-2-(tetrahydrofuran- 2-ylmeth- yl)isoindolin-1- one

402.1 53 rac-6-(2-fluoro- 4-(1-methyl-1H- 1,2,3-triazol-4- yl)benzyl)-2-(trans-2- hydroxycyclo- pentyl)-5- methylisoindolin- 1-one

421.1 54 6-(2-fluoro-4-(1- methyl-1H-1,2,3- triazol-4- yl)benzyl)-5-methyl-2- (tetrahydrofuran- 2-ylmeth- yl)isoindolin-1- one

421.2 55 rac-6-(4-(1,3- dimethyl-1H- pyrazol-4- yl)benzyl)-2- (trans-2-hydroxycyclo- pentyl)-5- methylisoindolin- 1-one

416.2

TABLE 1-12 Ex. No. IUPAC Name structure formula MS 56 6-(4-(1,3-dimethyl-1H- pyrazol-4- yl)benzyl)-5- methyl-2- (tetrahydro- furan-2-ylmethyl)iso- indolin-1-one

416.2 57 5-ethyl-6-(4- (1-methyl- 1H-pyrazol- 3-yl)benzyl)-2-(tetrahydro- furan-2- ylmethyl)iso- indolin-1-one

416.1 58 5-ethyl-6-(4- (1H-pyrazol- 1-yl)benzyl)- 2-(tetrahydro-furan-2- ylmethyl)iso- indolin-1-one

402.1 59 rac-5-ethyl- 2-(trans-2- hydroxy- cyclopentyl)- 6-(4-(1H-pyrazol-1- yl)benzyl)iso- indolin-1-one

402.1 60 5-chloro-6- (4-(1-methyl- 1H-1,2,3- triazol-4- yl)benzyl)-2-(tetrahydro- furan-2- ylmethyl)iso- indolin-1-one

423.1

TABLE 1-13 Ex. IUPAC No. Name structure formula MS 61 5- cyclopropyl-6-(4-(1- methyl-1H- 1,2,3-triazol- 4-yl)benzyl)- 2- (tetrahydro-furan-2- ylmethyl)iso- indolin-1- one

429.2 62 5- cyclopropyl- 6-(4-(1H- pyrazol-1- yl)benzyl)-2- (tetrahydro-furan-2- ylmethyl)iso- indolin-1- one

414.1 63 rac-5-ethyl- 2-(trans-2- hydroxy- cyclopentyl)- 6-(4-(1-methyl-1H- pyrazol-3- yl)ben- zyl)iso- indolin-1- one

416.2 64 rac-5- cyclopropyl- 2-(trans-2- hydroxy- cyclopentyl)- 6-(4-(1-methyl-1H- 1,2,3-triazol- 4-yl)ben- zyl)iso- indolin-1- one

429.2 65 rac-6-(2- fluoro-4-(1- methyl-1H- pyrazol-3- yl)benzyl)-2-(trans-2- hydroxy- cyclopentyl)- 5-methyliso- indolin-1- one

420.1

TABLE 1-14 Ex. No. IUPAC Name structure formula MS 66 6-(2-fluoro-4-(1-methyl-1H- pyrazol-3- yl)benzyl)-5- methyl-2- (tetrahydrofuran-2-ylmeth- yl)isoindolin-1- one

420.1 67 rac-2-(trans-2- hydroxycyclo- pentyl)-5-methyl- 6-(4-(1-methyl-1H-pyrazol-4- yl)ben- zyl)isoindolin-1- one

402.1 68 5-methyl-6-(4-(1- methyl-1H- pyrazol-4- yl)benzyl)-2-(tetrahydrofuran- 2-ylmeth- yl)isoindolin-1- one

402.1 69 rac-2-(trans-2- hydroxycyclo- pentyl)-4,5- dimethyl-6-(4-(1-methyl- 1H-pyrazol-4- yl)ben- zyl)isoindolin-1- one

416.2 70 6-(2-fluoro-4-(1- methyl-1H- pyrazol-3- yl)benzyl)-4,5-dimethyl-2- (tetrahydrofuran- 2-ylmeth- yl)isoindolin-1- one

434.2

TABLE 1-15 Ex. No. IUPAC Name structure formula MS 71 rac-6-(2-fluoro-4-(1-methyl- 1H-pyrazol-3- yl)benzyl)-2- (trans-2- hydroxycyclo-pentyl)-4,5- dimethyl- isoindolin-1- one

434.2 72 4-fluoro-5- methyl-6-(4- (1H-pyrazol-1- yl)benzyl)-2-(tetrahydro- furan-2- ylmethyl)iso- indolin-1-one

406.1 73 rac-5-chloro- 2-(trans-2- hydroxycyclo- pentyl)-6-(4-(1H-pyrazol-1- yl)benzyl)iso- indolin-1-one

408.1 74 5-chloro-6-(4- (1H-pyrazol- 1-yl)benzyl)- 2-(tetrahydro-furan-2- ylmeth- yl)isoindolin- 1-one

408.1 75 rac-5-chloro- 2-(trans-2- hydroxy- cyclohexyl)- 6-(4-(1-methyl-1H- pyrazol-4- yl)ben- zyl)isoindolin- 1-one

436.1

TABLE 1-16 Ex. No. IUPAC Name structure formula MS 76 rac-5-chloro-2-(trans-2- hydroxycyclo- pentyl)-6-(4- (1-methyl-1H- pyrazol-4-yl)benzyl)iso- indolin-1-one

422.0 77 5-chloro-6-(4- (1-methyl-1H- pyrazol-4- yl)benzyl)-2-(tetrahydro- furan-2- ylmethyl)iso- indolin-1-one

422.0 78 rac-4-fluoro- 2-(trans-2- hydroxycyclo- hexyl)-5- methyl-6-(4-(1H-pyrazol-1- yl)benzyl)iso- indolin-1-one

420.1 79 rac-4-fluoro- 2-(trans-2- hydroxycyclo- pentyl)-5- methyl-6-(4-(1H-pyrazol-1- yl)benzyl)iso- indolin-1-one

406.1 80 4,5-dimethyl-6- (4-(1H-pyrazol- 1-yl)benzyl)-2- (tetrahydro-furan-2- ylmethyl)iso- indolin-1-one

402.1

TABLE 1-17 Ex. No. IUPAC Name structure formula MS 81 4-methyl-1-oxo-6-(4-(1H- pyrazol-1- yl)benzyl)-2- (tetrahydro- furan-2-ylmethyl)iso- indoline-5- carbonitrile

413.2 82 rac-2-(trans-2- hydroxycyclo- hexyl)-4,5- dimethyl-6-(4-(1-methyl-1H- pyrazol-3- yl)benzyl)iso- indolin-1-one

430.2 83 rac-2-(trans-2- hydroxycyclo- pentyl)-4,5- dimethyl-6-(4-(1-methyl-1H- pyrazol-3- yl)benzyl)iso- indolin-1-one

416.2 84 4,5-dimethyl-6- (4-(1-methyl- 1H-pyrazol-4- yl)benzyl)-2-(tetrahydro- furan-2-ylmeth- yl)isoindolin-1- one

416.2 85 4,5-dimethyl-6- (4-(1-methyl- 1H-pyrazol-3- yl)benzyl)-2-(tetrahydro- furan-2-ylmeth- yl)isoindolin-1- one

416.2

TABLE 1-18 Ex. No. IUPAC Name structure formula MS 86 4-chloro-6-(4-(1H-pyrazol-1- yl)benzyl)-2- (tetrahydro- furan-2- ylmethyl)-5-(trifluorometh- yl)isoindolin- 1-one

476.1 87 rac-2-(trans-2- hydroxycyclo- pentyl)-4- methyl-1-oxo-6-(4-(1H- pyrazol-1- yl)benzyl)iso- indoline-5- carbonitrile

413.2 88 rac-4-chloro-2- (trans-2- hydroxycyclo- pentyl)-6-(4-(1H-pyrazol-1- yl)benzyl)-5- (trifluorometh- yl)isoindolin-1- one

476.2 89 rac-2-(trans-2- hydroxycyclo- hexyl)-4,5- dimethyl-6-(4-(1-methyl-1H- pyrazol-4- yl)benzyl)iso- indolin-1-one

430.2 90 4-chloro-5- methoxy-6-(4- (1H-pyrazol-1- yl)benzyl)-2-(tetrahydro- furan-2-ylmeth- yl)isoindolin-1- one

438.1

TABLE 1-19 Ex. No. IUPAC Name structure formula MS 91 rac-2-(trans-2-hydroxycyclo- pentyl)-5- methyl-6-(4- (6-methyl- pyridazin-4-yl)benzyl)iso- indolin-1-one

414.2 92 rac-4-chloro- 2-(trans-2- hydroxycyclo- pentyl)-5-methoxy-6-(4- (1H-pyrazol-1- yl)benzyl)iso- indolin-1-one

438.1 93 rac-4-chloro- 2-(trans-2- hydroxycyclo- hexyl)-5- methyl-6-(4-(1H-pyrazol-1- yl)benzyl)iso- indolin-1-one

436.1 94 rac-6-(4-(1,3- dimethyl-1H- pyrazol-4-yl)- 2-fluoroben-zyl)-2-(trans- 2-hydroxy- cyclohexyl)- 4,5-dimethyl- isoindolin-1-one

462.2 95 rac-6-(4-(1,3- dimethyl-1H- pyrazol-4-yl)-2- fluorobenzyl)-2-(trans-2- hydroxycyclo- pentyl)-4,5-dime- thylisoindolin-1- one

448.1

TABLE 1-20 Ex. structure No. IUPAC Name formula MS 964-fluoro-5-methoxy-6-(4- (1H-pyrazol-1-yl)benzyl)-2- (tetrahydrofuran-2-ylmethyl)isoindolin-1-one

422.1 97 rac-4-fluoro-2-(trans-2- hydroxycyclohexyl)-5-methoxy-6-(4-(1H-pyrazol-1- yl)benzyl)isoindolin-1-one

436.2 98 rac-4-fluoro-2-(trans-2- hydroxycyclopentyl)-5-methoxy-6-(4-(1H-pyrazol-1- yl)benzyl)isoindolin-1-one

422.1 99 rac-2-(trans-2- hydroxycyclohexyl)-5- methyl-6-(4-(2-methylpyridin-4- yl)benzyl)isoindolin-1-one

427.2 100  rac-2-(trans-2- hydroxycyclopentyl)-5- methyl-6-(4-(2-methylpyridin-4- yl)benzyl)isoindolin-1-one

413.2

TABLE 1-21 Ex. structure No. IUPAC Name formula MS 101 5-methyl-6-(4-(2-methylpyridin-4-yl)benzyl)- 2-(tetrahydrofuran-2-ylmethyl)isoindolin-1-one

413.2 102 rac-4-chloro-2-(trans-2- hydroxycyclopentyl)-5-methyl-6-(4-(1H-pyrazol-1- yl)benzyl)isoindolin-1-one

422.1 103 6-(2-fluoro-4-(1-methyl-1H- 1,2,3-triazol-4-yl)benzyl)-4,5-dimethyl-2- (tetrahydrofuran-2- ylmethyl)isoindolin-1-one

435.1 104 2-(2-hydroxy-2- methylpropyl)-5-methyl-6- (4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-one

376.1 105 5-ethyl-6-(4-(1-methyl-1H- 1,2,3-triazol-4-yl)benzyl)-2-(tetrahydrofuran-2- ylmethyl)isoindolin-1-one

417.1

TABLE 1-22 Ex. structure No. IUPAC Name formula MS 106rac-5-ethyl-2-(trans-2- hydroxycyclopentyl)-6-(4-(1-methyl-1H-1,2,3-triazol- 4-yl)benzyl)isoindolin-1- one

417.1 107 4-fluoro-2-((1S,2S)-2- hydroxycyclopentyl)-5-methyl-6-(4-(1H-pyrazol-1- yl)benzyl)isoindolin-1-one

406.1 108 4,5-dimethyl-6-(4-(1- methyl-1H-pyrazol-3- yl)benzyl)-2-((2R)-tetrahydrofuran-2- ylmethyl)isoinoldin-1-one

416.2 109 4,5-dimethyl-6-(4-(1- methyl-1H-pyrazol-3- yl)benzyl)-2-((2S)-tetrahydrofuran-2- ylmethyl)isoindolin-1-one

416.2 110 4,5-dimethyl-6-(4-(1- methyl-1H-1,2,3-triazol-4-yl)benzyl)-2-((2R)- tetrahydrofuran-2- ylmethyl)isoindolin-1-one

417.1

TABLE 1-23 Ex. structure No. IUPAC Name formula MS 111 4-fluoro-2-((1S,2S)-2- hydroxycyclo- pentyl)-5-methyl- 6-(4-(1-methyl- 1H-pyrazol-3-yl)benzyl) isoindolin-1-one

420.2 112 rac-3-fluoro- 4-((2-(trans-4- hydroxytetra- hydro-2H-pyran-3-yl)-6,7- dimethyl-3- oxo-2,3-dihydro- 1H-isoindol-5- yl)methyl)benzonitrile

395.2 113 rac-3-fluoro- 4-((2-(trans-4- hydroxytetra- hydro-2H-pyran-3-yl)-6,7- dimethyl-3- oxo-2,3- dihydro-1H- isoindol-5- yl)methyl)benzamide

413.2 114 2-(2-hydroxy- 2-methylpropyl)- 4,5-dimethyl-6- (4-(1-methyl-1H-pyrazol- 3-yl)benzyl) isoindolin-1-one

404.2 115 6-(2-fluoro-4- (1H-pyrazol-1- yl)benzyl)-4,5-dimethyl-2-((2S)- tetrahydrofuran-2- ylmethyl) isoindolin-2-one

420.2

TABLE 1-24 Ex. structure No. IUPAC Name formula MS 1165-ethyl-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-6-[4-(1-methyl-1H-pyrazol-3-yl)benzyl]-2,3-dihydro-1H-isoindol-1- one Alias;1,5-anhydro-2,4-dideoxy-2-(5- ethyl-6-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-1-oxo-1,2-dihydro-2H-isoindol- 2-yl)-L-threo-pentitol

432.1 117 5-ethyl-2-[(3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl]-6-[4-(1-methyl-1H-pyrazol-3-yl)benzyl]-2,3-dihydro-1H-isoindol-1- one Alias;1,5-anhydro-2,4-dideoxy-2-(5- ethyl-6-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-1-oxo-1,3-dihydro-2H-isoindol- 2-yl)-D-threo-pentitol

432.1 118 5-ethyl-2-(2-hydroxy-2-methylpropyl)-6-(4-(1-methyl-1H-1,2,3-triazol-4- yl)benzyl)isoindolin-1-one

405.1 119 5-ethyl-2-((1S,2S)-2-hydroxycyclopentyl)-6-(4-(1-methyl-1H-1,2,3-triazol-4- yl)benzyl)isoindolin-1-one

417.0 120 5-ethyl-2-((1S,2S)-2-hydroxycyclopentyl)-6-(4-(1-methyl-1H-pyrazol-3- yl)benzyl)isoindolin-1-one

416.1

TABLE 1-25 Ex. structure No. IUPAC Name formula MS 1216-(2-fluoro-4-(1H-pyrazol-1- yl)benzyl)-2-(2-hydroxy-2-methylpropyl)-4,5- dimethylisoindolin-1-one

408.1 122 2-((1S,2S)-2-hydroxycyclopentyl)-6- (4-methoxybenzyl)-4,5-dimethylisoindolin-1-one

366.1 123 2-fluoro-4-((2-((1S,2S)-2- hydroxycyclopentyl)-6,7-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-5- yl)methyl)-N-methylbenzamide

411.1 124 3-fluoro-4-({2-[(3S,4S)-4- hydroxytetrahydro-2H-pyran-3-yl]-6,7-dimethyl-3-oxo-2,3-dihydro-1H- isoindol-5-yl}methyl)benzonitrileAlias; 1,5-anhydro-2-(6-(4-cyano-2- fluorobenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,4- dideoxy-L-threo-pentitol

395.1 125 3-fluoro-4-((2-((1S,2S)-2- hydroxycyclopentyl)-6,7-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-5- yl)benzyl)benzonitrile

379.2

TABLE 1-26 Ex. structure No. IUPAC Name formula MS 1263-fluoro-4-((2-(2-hydroxy-2- methylpropyl)-6,7-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-5- yl)methyl)benzonitrile

367.1 127 4-fluoro-2-(2-hydroxy-2-methylpropyl)-5-methyl-6-(4-(1H-pyrazol-1- yl)benzyl)isoindolin-1-one

394.1 128 5-ethyl-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindol-1-one Alias;1,5-anhydro-2,4-dideoxy-2-(5- ethyl-1-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)-1,3-dihydro-2H-isoindol-2- yl)-L-threo-pentitol

418.0 129 5-ethyl-2-(2-hydroxy-2-methylpropyl)-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1- one

390.1 130 4-chloro-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-methyl-6-[4-(1H- pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindol-1-one Alias; 1,5-anhydro-2-(4-chloro-5-methyl-1-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)-1,3-dihydro-2H-isoindol-2-yl)-2,4-dideoxy-L- threo-pentitol

438.0

TABLE 1-27 Ex. structure No. IUPAC Name formula MS 1314-chloro-2-((1S,2S)-2- hydroxycyclopentyl)-5- methyl-6-(4-(1H-pyrazol-1-yl)benzyl) isoindolin-1-one

422.0 132 4-chloro-2-(2-hydroxy- 2-methylpropyl)-5- methyl-6-(4-(1H-pyrazol-1-yl)benzyl) isoindolin-1-one

410.0 133 2-(3-hydroxy-3- methylbutan-2-yl)- 5-methyl-6-(4-(1H-pyrazol-1- yl)benzyl)isoindolin- 1-one

390.1 134 2-((1S,2S)-2- hydroxycyclopentyl)- 4,5-dimethyl-6-((6-methylpyridin-3- yl)methyl)isoindolin- 1-one

351.2 135 2-(2-fluorophenyl)-5- methyl-6-(4-(1H- pyrazol-1-yl)benzyl)isoindolin-1-one

398.0

TABLE 1-28 Ex. structure No. IUPAC Name formula MS 1364,5-dimethyl-6-((6-(1H-pyrazol-1- yl)pyridin-3-yl)methyl)-2-((2S)-tetrahydrofuran-2-ylmethyl)isoindolin-1- one

403.1 137 5-ethyl-2-(2-hydroxy-2-methylpropyl)-6-(4-(1-methyl-1H-pyrazol-3- yl)benzyl)isoindolin-1-one

404.1 138 2-fluoro-4-((2-(2-hydroxy-2-methylpropyl)-6,7-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)methyl)-N- methylbenzamide

399.0 139 4-((6,7-dimethyl-3-oxo-2-((2S)-tetrahydrofuran-2-ylmethyl)-2,3-dihydro-1H-isoindol-5-yl)methyl)-2-fluoro-N- methylbenzamide

411.1 140 4-fluoro-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-methyl-6-[4-(1-methyl-1H-pyrazol-3-yl)benzyl]-2,3-dihydro-1H- isoindol-1-one Alias;1,5-anhydro-2,4-dideoxy-2-(4- fluoro-5-methyl-6-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

436.0

TABLE 1-29 Ex. structure No. IUPAC Name formula MS 1412-((1S,2S)-2-hydroxycyclohexyl)-6-(4-methoxybenzyl)-4,5-dimethylisoindolin-1- one

380.1 142 6-(4-ethoxybenzyl)-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-4,5-dimethyl-2,3-dihydro-1H-isoinol-1-one Alias;1,5-anhydro-2,4-dideoxy-2-(6-(4- ethoxybenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

396.1 143 2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-4,5-dimethyl-6-[4-(propan-2-yloxy)benzyl]-2,3-dihydro-1H-isoindol-1- one Alias;1,5-anhydro-2,4-dideoxy-2-(6-(4-isopropoxybenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

410.1 144 5-ethyl-6-[2-fluoro-4-(1H-pyrazol-1-yl)benzyl]-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-2,3-dihydro-1H-isoindol-1- one Alias;1,5-anhydro-2,4-dideoxy-2-(5-ethyl-6-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo- pentitol

436.2 145 5-ethyl-6-(2-fluoro-4-(1H-pyrazol-1- yl)benzyl)-2-((1S,2S)-2-hydroxycyclopentyl)isoindolin-1-one

420.3

TABLE 1-30 Ex. structure No. IUPAC Name formula MS 1465-ethyl-6-(2-fluoro-4-(1H-pyrazol-1- yl)benzyl)-2-(2-hydroxy-2-methylpropyl)isoindolin-1-one

408.1 147 2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-4,5-dimethyl-6-[4- (trifluoromethoxy)benzyl]-2,3-dihydro-1H-isoindol-1-one Alias; 1,5-anhydro-2,4-dideoxy-2-(4,5-dimethyl-1-oxo-6-(4- (trifluoromethoxy)benzyl)-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

436.1 148 5-ethyl-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-6-(4-methoxybenzyl)-2,3- dihydro-1H-isoindol-1-one Alias;1,5-anhydro-2,4-dideoxy-2-(5-ethyl-6-(4-methoxybenzyl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

382.2 149 6-((6-ethylpyridin-3-yl)methyl)-2-((1S,2S)-2-hydroxycyclohexyl)-4,5- dimethylisoindolin-1-one

379.3 150 4-fluoro-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-6-(4-methoxybenzyl)-5-methyl-2,3-dihydro-1H-isoindol-1-one Alias;1,5-anhydro-2,4-dideoxy-2-(4- fluoro-6-(4-methoxybenzyl)-5-methyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo- pentitol

386.1

TABLE 1-31 Ex. structure No. IUPAC Name formula MS 1514-chloro-2-((1S,2S)- 2-hydroxycyclohexyl)- 6-(4-methoxybenzyl)-5-methylisoindolin-1-one

400.1 152 4-chloro-2-((1S,2S)- 2-hydroxycyclopentyl)-6-(4-methoxybenzyl)-5- methylisoindolin-1-one

386.1 153 2-(3-fluoropyridin-2-yl)- 4,5-dimethyl-6-(4-(1H- pyrazol-1-yl)benzyl)isoindolin- 1-one

413.1 154 4-fluoro-2-((1S,2S)- 2-hydroxycyclohexyl)-6-(4-methoxybenzyl)-5- methylisoindolin-1-one

384.2 155 4-((2-((1S,2S)-2- hydroxycyclohexyl)- 6,7-dimethyl-3-oxo-2,3-dihydro-1H- isoindol-5- yl)methyl)benzonitrile

375.2

TABLE 1-32 Ex. structure No. IUPAC Name formula MS 1564-({2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-6,7-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl}methyl)benzonitrile Alias;1,5-anhydro-2-(6-(4-cyanobenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,4-dideoxy-L-threo-pentitol

377.3 157 4-chloro-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-methoxy-6-(4-methoxybenzyl)- 2,3-dihydro-1H-isoindol-1-oneAlias; 1,5-anhydro-2,4-dideoxy-2-(4-fluoro-5-methoxy-6-(4-methoxybenzyl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

402.1 158 6-(3-fluoro-4-methoxybenzyl)-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-4,5-dimethyl-2,3-dihydro-1H-isoindol-1-one Alias;1,5-anhydro-2,4-dideoxy-2-(6-(3-fluoro-4-methoxybenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo- pentitol

400.1 159 2-(2-fluorophenyl)-4,5-dimethyl-6-(4-(1H-pyrazol-1-yl)benzyl)isoindolin-1-one

412.2 160 2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-6-(4-methoxy-3-methylbenzyl)-4,5-dimethyl-2,3-dihydro-1H-isoindol-1-one Alias;1,5-anhydro-2,4-dideoxy-2-(6-(4-methoxy-3-methylbenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo- pentitol

396.2

TABLE 1-33 Ex. structure No. IUPAC Name formula MS 1614-fluoro-2-((1S,2S)-2-hydroxycyclohexyl)-5-methoxy-6-(4-methoxybenzyl)isoindol-1- one

400.2 162 2-(5-chloro-3-fluoropyridin-2-yl)-4,5-dimethyl-6-(4-(1H-pyrazol-1- yl)benzyl)isoindolin-1-one

447.1 163 6-(2-fluoro-4-methoxybenzyl)-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-4,5-dimethyl-2,3-dihydro-1H-isoindol-1-one Alias;1,5-anhydro-2,4-dideoxy-2-(6-(2- fluoro-4-methoxybenzyl)-4,5-dimethyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo- pentitol

400.1 164 2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-6-(4-methoxybenzyl)-5-methyl-2,3- dihydro-1H-isoindol-1-one Alias;1,5-anhydro-2,4-dideoxy-2-(6-(4-methoxybenzyl)-5-methyl-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-L-threo-pentitol

368.2 165 rac-2-(trans-4-hydroxytetrahydro-2H-pyran-3-yl)-6-(4-methoxybenzyl)-4,5-dimethyl- 2,3-dihydro-1H-isoindol-1-one

382.2

TABLE 1-34 Ex. structure No. IUPAC Name formula MS 166 2-[(3S,4S)-4-hydroxytetrahydro-2H- pyran-3-yl]-5-methoxy- 6-(4-methoxybenzyl)-4-methyl-2,3-dihydro-1H- isoindol-1-one Alias; 1,5-anhydro-2,4-dideoxy-2-(5-methoxy- 6-(4-methoxybenzyl)-4- methyl-1-oxo-1,3-dihydro-2H-isoindol-2- yl)-L-threo-pentitol

398.2 167 2-((1S,2S)-2- hydroxycyclohexyl)- 6-(4-methoxybenzyl)-5-methylisoindolin-1-one

366.1 168 2-(3-hydroxy-3- methylbutan-2-yl)-6-(4- methoxybenzyl)-4,5-dimethylisoindolin-1- one

368.2

Formulation Example 1 (1) Compound obtained in Example 1 10.0 g (2)Lactose 60.0 g (3) Cornstarch 35.0 g (4) Gelatin 3.0 g (5) Magnesiumstearate 2.0 g

A mixture of the compound (10.0 g) obtained in Example 1, lactose (60.0g) and cornstarch (35.0 g) is passed through a 1 mm mesh sieve by using10 wt % aqueous gelatin solution (30 mL) (3.0 g as gelatin) and thegranules are dried at 40° C. and sieved again. The obtained granules aremixed with magnesium stearate (2.0 g) and the mixture is compressed. Theobtained core tablets are coated with a sugar coating of an aqueoussuspension of saccharose, titanium dioxide, talc and gum arabic. Thecoated tablets are glazed with beeswax to give 1000 coated tablets.

Formulation Example 2 (1) Compound obtained in Example 1 10.0 g (2)Lactose 70.0 g (3) Cornstarch 50.0 g (4) Soluble starch 7.0 g (5)Magnesium stearate 3.0 g

The compound (10.0 g) obtained in Example 1 and magnesium stearate (3.0g) are granulated using aqueous soluble starch solution (70 mL) (7.0 gas soluble starch), and the obtained granules are dried, and mixed withlactose (70.0 g) and cornstarch (50.0 g). The mixture is compressed togive 1000 tablets.

Experimental Example 1 Measurement of M1 Receptor Positive AllostericModulator (M1PAM) Activity

The activity of a test compound in the presence of acetylcholine at EC20concentration (final concentration 0.6-0.8 nM), which affords an actioncorresponding to about 20% of the maximum activity, was measured as PAMactivity. The method is as follows. CHO-K1 cells stably expressing ahuman M1 receptor (hCHRM1) were plated on a 384-well black clear bottomplate (BD Falcon) at 5,000 cells/well, and cultured in an incubator at37° C., 5% CO₂ for 1 day. The medium in the cell plate was removed, andassay buffer A (Recording medium (DOJINDO LABORATORIES), 0.1% BSA (WakoPure Chemical Industries, Ltd.), 2.5 μg/mL Fluo-4 AM (DOJINDOLABORATORIES), 0.08% Pluronic F127 (DOJINDO LABORATORIES), 1.25 mMprobenecid (DOJINDO LABORATORIES)) containing a calcium indicator wasadded at 30 μL/well. The cells were left standing in the incubator at37° C., 5% CO₂ for 30 min, and further left standing at room temperaturefor 30 min. A test compound prepared by diluting with assay buffer B(HBSS (Invitrogen), 20 mM HEPES (Invitrogen), 0.1% BSA) containing2.4-3.2 nM acetylcholine was added at 10 μL/well, and the fluorescencewas measured by FLIPRtetra (Molecular Devices) for 1 min every 1 second.With the definition that the amount of change in the fluorescence onaddition of acetylcholine (final concentration 1 μM) is 100% and that onaddition of DMSO instead of a test compound is 0%, the activity (%) ofthe test compound was calculated, and the inflection point in theconcentration-dependent curve of the test compound was calculated as IPvalues. The results are shown in Table 2.

TABLE 2-1 Example IP value activity (%) No. (nM) at 10 μM 1 750 111 2 86109 3 15 106 4 19 98 5 8.2 102 6 5.3 101 7 180 107 8 290 90 9 43 102 1066 106 11 13 105 12 7.7 91 13 7.9 104 14 1.2 94 15 11 103 16 12 94 17 1890 18 10 88 19 2 101 20 5.5 109 21 6.2 106 22 32 110 23 46 100 24 4.3 8825 10 90 26 9.2 99 28 4.8 106 29 9.5 102 32 5.6 99 33 37 95 34 18 108 353.9 103 36 83 107 40 37 97

TABLE 2-2 Example IP value activity (%) No. (nM) at 10 μM 41 30 97 429.2 115 43 98 110 47 3 99 48 31 102 49 31 97 51 42 86 53 28 103 54 37 9255 98 101 58 95 100 59 34 100 60 72 94 61 35 97 62 95 103 63 45 99 64 22104 67 26 93 68 96 95 69 13 95 71 56 100 75 23 97 78 8.8 95 79 72 93 8014 90

TABLE 2-3 Example IP value activity (%) No. (nM) at 10 μM 82 5.7 91 8313 92 84 52 104 85 41 105 88 85 98 89 5.7 94 91 38 95 92 60 91 93 5.6 9494 9.5 92 95 26 92 97 5.3 96 99 16 103 100 94 101 102 13 91 103 6 94 10454 101 105 10 92 106 11 92 107 14 102 109 23 100 110 24 77 111 26 103112 30 93 113 1.5 82 114 15 96 115 25 92 116 6.1 111 118 25 106 119 3.191 120 25 93

TABLE 2-4 Example IP value activity (%) No. (nM) at 10 μM 121 22 89 1232.1 90 124 16 86 125 73 93 127 59 104 128 5 97 129 53 100 130 2.2 94 13112 100 132 7.3 87 133 35 87 136 75 100 138 25 106 139 14 102 140 2 93141 18 106 142 31 106 144 23 97 148 63 89 149 16 99 150 14 89 151 16 92152 47 91 153 57 92 154 22 100 155 7.1 100 156 4.3 80 157 84 97 158 28111 160 47 112 161 32 94 162 66 95 163 51 108 164 62 102 165 36 103 16730 95

Experimental Example 2 Measurement of Myo-Inositol 1 Phosphate (IP1)

Animals used were male Long-Evans rats. They were used after acclimationfor at least 1 week. Test compounds were suspended in 0.5% aqueousmethylcellulose solution, and the suspension was orally administered tothe rats. At a certain period of time after the oral administration, thesolution prepared by dissolving lithium chloride in saline wassubcutaneously administered into the rats. At a certain period of timeafter the subcutaneously administration, their bilateral hippocampi wereisolated from the rats, and the wet weight thereof was measured. Thehippocampi were homogenized with HEPES buffer, followed bycentrifugation. The IP1 and protein concentrations in the supernatantwere measured by IP-One HTRF assay kit (Cisbio Bioassays) and BCAprotein assay kit (Thermo Scientific), respectively. The level of theIP1 production was expressed as the ratio of the concentration of IP1 tothat of protein. The increase rate of the IP1 production was shown as arelative value when Vehicle administration group as 100%. The resultsare shown in Table 3.

TABLE 3 increase rate at 10 mg/kg test compound (% of Vehicle) Example18 40 Example 20 108 Example 25 32

Experimental Example 3 Novel Object Recognition Test

Novel object recognition test is comprised of two trials called theacquisition and the retention trials. Scopolamine-induced memorydeficits models were used for the test, and animals used were maleLong-Evans rats (7-week-old). On the day before the test, foracclimation, the rats were allowed to freely move about the test box(40×40×50 cm) for 10 minutes. On the test day, the rats were acclimatedto the test room for about 1 hr prior to the test. The test compoundswere orally administered to the rats in a single dose 2 hr before theacquisition trial. For induction of learning and memory deficits,scopolamine (0.1 mg/kg) was subcutaneously administered into the rats 30min before the acquisition trial. For the acquisition trial, twoidentical objects (A1, A2) were placed in the test box. The rats wereput in the test box for 3 min, and the duration exploring each objectwas measured. The retention trial was performed 4 hr after theacquisition trial. For the retention trial, the familiar object (A3)used for the acquisition trial and the novel object (B) different shapefrom A3 were placed in the test box. The rats were put in the test boxfor 3 min. The duration exploring each object in the acquisition trialand the retention trial, and the exploration rate (%) of novel objectwas calculated. The exploration rate (%) of novel object was expressedas (the duration exploring the novel object)/[(the duration exploringthe novel object)+(the duration exploring the familiar object)]×100(%)at mean±standard error. The results are shown below.

exploration rate (%) of novel object

control: 63.35±1.59%

solvent-scopolamine group: 52.08±2.47%

Example 18 (3 mg/kg)-scopolamine group: 59.11±3.87%

control: 66.4±2.3%

solvent-scopolamine group: 50.4±2.4%

Example 20 (3 mg/kg)-scopolamine group: 61.2±3.1%

control: 62.37±3.24%

solvent-scopolamine group: 48.39±2.01%

Example 25 (10 mg/kg)-scopolamine group: 57.55±5.03%

INDUSTRIAL APPLICABILITY

The compound of the present invention is useful as a cholinergicmuscarinic M1 receptor positive allosteric modulator, or a medicamentsuch as an agent for the prophylaxis or treatment of Alzheimer'sdisease, schizophrenia, pain, sleep disorder, Parkinson's diseasedementia, dementia with Lewy bodies and the like.

This application is based on patent application No. 2014-089585 filed onApr. 23, 2014 in Japan, the contents of which are encompassed in fullherein.

The invention claimed is: 1.4-Fluoro-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindol-1-one,or a salt thereof.
 2. A medicament comprising4-Fluoro-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-methyl-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindol-1-oneor a salt thereof, and a pharmaceutically acceptable carrier.